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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Review Article

The Endeavours in RAS Inhibition - the Past, Present, and Future

Author(s): Javeena Hussain, Sivapriya Kirubakaran* and Srimadhavi Ravi

Volume 20, Issue 29, 2020

Page: [2708 - 2722] Pages: 15

DOI: 10.2174/1568026620666200903163044

Price: $65

Abstract

KRAS mutations are known to be the most recurrent gain-of-function changes instigated in patients with cancer. The RAS gene family is often mutated in most of the human cancers, and the pursuit of inhibitors that bind to mutant RAS continues as a foremost target. RAS is a small GTPase that controls numerous cellular functions, including cell proliferation, growth, survival, and gene expression. RAS is hence closely engaged in cancer pathogenesis. The recent achievements in the discovery of RAS inhibitors imply that the inhibition of RAS oncogene may soon go into clinical trials. This review article describes the role of RAS in cancer drug discovery, the diverse methodologies used to develop direct or indirect RAS inhibitors, and emphasize the current accomplishments in the progress of novel RAS inhibitors. In short, this review focuses on the different attributes of RAS that have been targeted by a range of inhibitors consisting of membrane localization, the active form of RAS, downstream regulator binding, and nucleotide exchange binding. A detailed explanation of RAS and its involvement in cancer drug discovery together with historical aspects are mentioned first followed by a brief outline of the different approaches to target RAS.

Keywords: Cancer, Small GTPase, RAS mutation, GTP-binding protein, Small molecule, Inhibitor.

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[1]
Heng, H.H. The genomic landscape of cancer.Ecology and Evolution of Cancer; Academic Press: London, 2017, pp. 69-86.
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[http://dx.doi.org/10.3322/caac.21442] [PMID: 29313949]
[3]
Spiegel, J.; Cromm, P.M.; Zimmermann, G.; Grossmann, T.N.; Waldmann, H. Small-molecule modulation of Ras signaling. Nat. Chem. Biol., 2014, 10(8), 613-622.
[http://dx.doi.org/10.1038/nchembio.1560] [PMID: 24929527]
[4]
Malumbres, M.; Barbacid, M. RAS oncogenes: the first 30 years. Nat. Rev. Cancer, 2003, 3(6), 459-465.
[http://dx.doi.org/10.1038/nrc1097] [PMID: 12778136]
[5]
Harvey, J.J. An unidentified virus which causes the rapid production of tumours in mice. Nature, 1964, 204, 1104-1105.
[http://dx.doi.org/10.1038/2041104b0]
[6]
Kirsten, W.H.; Mayer, L.A. Morphologic responses to a murine erythroblastosis virus. J. Natl. Cancer Inst., 1967, 39(2), 311-335.
[PMID: 18623947]
[7]
Hager, G.L.; Chang, E.H.; Chan, H.W.; Garon, C.F.; Israel, M.A.; Martin, M.A.; Scolnick, E.M.; Lowy, D.R. Molecular cloning of the Harvey sarcoma virus closed circular DNA intermediates: initial structural and biological characterization. J. Virol., 1979, 31(3), 795-809.
[http://dx.doi.org/10.1128/JVI.31.3.795-809.1979] [PMID: 229252]
[8]
Tsuchida, N.; Uesugi, S. Structure and functions of the Kirsten murine sarcoma virus genome: molecular cloning of biologically active Kirsten murine sarcoma virus DNA. J. Virol., 1981, 38(2), 720-727.
[http://dx.doi.org/10.1128/JVI.38.2.720-727.1981] [PMID: 6264139]
[9]
Chang, E.H.; Gonda, M.A.; Ellis, R.W.; Scolnick, E.M.; Lowy, D.R. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proc. Natl. Acad. Sci. USA, 1982, 79(16), 4848-4852.
[http://dx.doi.org/10.1073/pnas.79.16.4848] [PMID: 6289320]
[10]
Ellis, R.W.; Defeo, D.; Shih, T.Y.; Gonda, M.A.; Young, H.A.; Tsuchida, N.; Lowy, D.R.; Scolnick, E.M. The p21 src genes of Harvey and Kirsten sarcoma viruses originate from divergent members of a family of normal vertebrate genes. Nature, 1981, 292(5823), 506-511.
[http://dx.doi.org/10.1038/292506a0] [PMID: 6265801]
[11]
Shimizu, K.; Goldfarb, M.; Perucho, M.; Wigler, M. Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line. Proc. Natl. Acad. Sci. , 1983, 80, 383-387.
[http://dx.doi.org/10.1073/pnas.80.2.383]
[12]
Hall, A.; Marshall, C.J.; Spurr, N.K.; Weiss, R.A. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1. Nature, 1983, 303(5916), 396-400.
[http://dx.doi.org/10.1038/303396a0] [PMID: 6304521]
[13]
McGrath, J.P.; Capon, D.J.; Goeddel, D.V.; Levinson, A.D. Comparative biochemical properties of normal and activated human ras p21 protein. Nature, 1984, 310(5979), 644-649.
[http://dx.doi.org/10.1038/310644a0] [PMID: 6147754]
[14]
Gibbs, J.B.; Sigal, I.S.; Poe, M.; Scolnick, E.M. Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc. Natl. Acad. Sci. USA, 1984, 81(18), 5704-5708.
[http://dx.doi.org/10.1073/pnas.81.18.5704] [PMID: 6148751]
[15]
Sweet, R.W.; Yokoyama, S.; Kamata, T.; Feramisco, J.R.; Rosenberg, M.; Gross, M. The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity. Nature, 1984, 311(5983), 273-275.
[http://dx.doi.org/10.1038/311273a0] [PMID: 6148703]
[16]
Tabin, C.J.; Bradley, S.M.; Bargmann, C.I.; Weinberg, R.A.; Papageorge, A.G.; Scolnick, E.M.; Dhar, R.; Lowy, D.R.; Chang, E.H. Mechanism of activation of a human oncogene. Nature, 1982, 300(5888), 143-149.
[http://dx.doi.org/10.1038/300143a0] [PMID: 6290897]
[17]
Reddy, E.P.; Reynolds, R.K.; Santos, E.; Barbacid, M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature, 1982, 300(5888), 149-152.
[http://dx.doi.org/10.1038/300149a0] [PMID: 7133135]
[18]
Parada, L.F.; Tabin, C.J.; Shih, C.; Weinberg, R.A.; Human, E.J. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature, 1982, 297(5866), 474-478.
[http://dx.doi.org/10.1038/297474a0] [PMID: 6283357]
[19]
Der, C.J.; Krontiris, T.G.; Cooper, G.M. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc. Natl. Acad. Sci. USA, 1982, 79(11), 3637-3640.
[http://dx.doi.org/10.1073/pnas.79.11.3637] [PMID: 6285355]
[20]
Shimizu, K.; Goldfarb, M.; Suard, Y.; Perucho, M.; Li, Y.; Kamata, T.; Feramisco, J.; Stavnezer, E.; Fogh, J.; Wigler, M.H. Three human transforming genes are related to the viral ras oncogenes. Proc. Natl. Acad. Sci. USA, 1983, 80(8), 2112-2116.
[http://dx.doi.org/10.1073/pnas.80.8.2112] [PMID: 6572964]
[21]
Shimizu, K.; Birnbaum, D.; Ruley, M.A.; Fasano, O.; Suard, Y.; Edlund, L.; Taparowsky, E.; Goldfarb, M.; Wigler, M. Structure of the Ki-ras gene of the human lung carcinoma cell line Calu-1. Nature, 1983, 304(5926), 497-500.
[http://dx.doi.org/10.1038/304497a0] [PMID: 6308465]
[22]
Shih, T.Y.; Weeks, M.O.; Young, H.A.; Scholnick, E.M. Identification of a sarcoma virus-coded phosphoprotein in nonproducer cells transformed by Kirsten or Harvey murine sarcoma virus. Virology, 1979, 96(1), 64-79.
[http://dx.doi.org/10.1016/0042-6822(79)90173-9] [PMID: 223311]
[23]
Scolnick, E.M.; Papageorge, A.G.; Shih, T.Y. Guanine nucleotide-binding activity as an assay for src protein of rat-derived murine sarcoma viruses. Proc. Natl. Acad. Sci. USA, 1979, 76(10), 5355-5359.
[http://dx.doi.org/10.1073/pnas.76.10.5355] [PMID: 228288]
[24]
Kamata, T.; Feramisco, J.R. Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of ras oncogene proteins. Nature, 1984, 310(5973), 147-150.
[http://dx.doi.org/10.1038/310147a0] [PMID: 6610834]
[25]
Mulcahy, L.S.; Smith, M.R.; Stacey, D.W. Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature, 1985, 313(5999), 241-243.
[http://dx.doi.org/10.1038/313241a0] [PMID: 3918269]
[26]
Willingham, M.C.; Pastan, I.; Shih, T.Y.; Scolnick, E.M. Localization of the src gene product of the Harvey strain of MSV to plasma membrane of transformed cells by electron microscopic immunocytochemistry. Cell, 1980, 19(4), 1005-1014.
[http://dx.doi.org/10.1016/0092-8674(80)90091-4] [PMID: 6247068]
[27]
Smith, M.R.; DeGudicibus, S.J.; Stacey, D.W. Requirement for c-ras proteins during viral oncogene transformation. Nature, 1986, 320(6062), 540-543.
[http://dx.doi.org/10.1038/320540a0] [PMID: 2938016]
[28]
Manne, V.; Bekesi, E.; Kung, H.F. Ha-ras proteins exhibit GTPase activity: point mutations that activate Ha-ras gene products result in decreased GTPase activity. Proc. Natl. Acad. Sci. USA, 1985, 82(2), 376-380.
[http://dx.doi.org/10.1073/pnas.82.2.376] [PMID: 2982154]
[29]
Trahey, M.; McCormick, F. A Cytoplasmic protein stimulates normal n-ras p21 gtpase, but does not affect oncogenic mutants. Science (80-. ),, 1987, 238, 542-545.
[30]
Stevens, K.N.; Wang, X.; Fredericksen, Z.; Pankratz, V.S.; Cerhan, J.; Vachon, C.M.; Olson, J.E.; Couch, F.J. Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer. Breast Cancer Res. Treat., 2011, 129(2), 617-622.
[http://dx.doi.org/10.1007/s10549-011-1587-y] [PMID: 21607584]
[31]
Burns, M.C.; Sun, Q.; Daniels, R.N.; Camper, D.; Kennedy, J.P.; Phan, J.; Olejniczak, E.T.; Lee, T.; Waterson, A.G.; Rossanese, O.W.; Fesik, S.W. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc. Natl. Acad. Sci. USA, 2014, 111(9), 3401-3406.
[http://dx.doi.org/10.1073/pnas.1315798111] [PMID: 24550516]
[32]
Robinson, L.C.; Gibbs, J.B.; Marshall, M.S.; Sigal, I.S.; Tatchell, K. CDC25: A component of the ras-adenylate cyclase pathway in saccharomyces cerevisiae. Science (80-. ), , 1987, 235, 1218-1221.
[33]
Rodriguez-Viciana, P.; Warne, P.H.; Dhand, R.; Vanhaesebroeck, B.; Gout, I.; Fry, M.J.; Waterfield, M.D.; Downward, J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature, 1994, 370(6490), 527-532.
[http://dx.doi.org/10.1038/370527a0] [PMID: 8052307]
[34]
Sjölander, A.; Yamamoto, K.; Huber, B.E.; Lapetina, E.G. Association of p21ras with phosphatidylinositol 3-kinase. Proc. Natl. Acad. Sci. USA, 1991, 88(18), 7908-7912.
[http://dx.doi.org/10.1073/pnas.88.18.7908] [PMID: 1716764]
[35]
Maffucci, T.; Piccolo, E.; Cumashi, A.; Iezzi, M.; Riley, A.M.; Saiardi, A.; Godage, H.Y.; Rossi, C.; Broggini, M.; Iacobelli, S.; Potter, B.V.L.; Innocenti, P.; Falasca, M. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects. Cancer Res., 2005, 65(18), 8339-8349.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-0121] [PMID: 16166311]
[36]
Su, F.; Viros, A.; Milagre, C.; Trunzer, K.; Bollag, G.; Spleiss, O.; Reis-Filho, J.S.; Kong, X.; Koya, R.C.; Flaherty, K.T.; Chapman, P.B.; Kim, M.J.; Hayward, R.; Martin, M.; Yang, H.; Wang, Q.; Hilton, H.; Hang, J.S.; Noe, J.; Lambros, M.; Geyer, F.; Dhomen, N.; Niculescu-Duvaz, I.; Zambon, A.; Niculescu-Duvaz, D.; Preece, N.; Robert, L.; Otte, N.J.; Mok, S.; Kee, D.; Ma, Y.; Zhang, C.; Habets, G.; Burton, E.A.; Wong, B.; Nguyen, H.; Kockx, M.; Andries, L.; Lestini, B.; Nolop, K.B.; Lee, R.J.; Joe, A.K.; Troy, J.L.; Gonzalez, R.; Hutson, T.E.; Puzanov, I.; Chmielowski, B.; Springer, C.J.; McArthur, G.A.; Sosman, J.A.; Lo, R.S.; Ribas, A.; Marais, R. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med., 2012, 366(3), 207-215.
[http://dx.doi.org/10.1056/NEJMoa1105358] [PMID: 22256804]
[37]
Dickson, B.; Sprenger, F.; Morrison, D.; Hafen, E. Raf functions downstream of Ras1 in the Sevenless signal transduction pathway. Nature, 1992, 360(6404), 600-603.
[http://dx.doi.org/10.1038/360600a0] [PMID: 1461284]
[38]
Van Aelst, L.; Barr, M.; Marcus, S.; Polverino, A.; Wigler, M. Complex formation between RAS and RAF and other protein kinases. Proc. Natl. Acad. Sci. USA, 1993, 90(13), 6213-6217.
[http://dx.doi.org/10.1073/pnas.90.13.6213] [PMID: 8327501]
[39]
Moodie, S.A.; Willumsen, B.M.; Weber, M.J.; Wolfman, A.A. Complexes of ras.gtp with raf-1 and mitogen-activated protein kinase kinase. Science (80-. ), 1993, 260, 1658-1661.
[40]
Warne, P.H.; Viciana, P.R.; Downward, J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature, 1993, 364(6435), 352-355.
[http://dx.doi.org/10.1038/364352a0] [PMID: 8332195]
[41]
Zhang, X-F.; Settleman, J.; Kyriakis, J.M.; Takeuchi-Suzuki, E.; Elledge, S.J.; Marshall, M.S.; Bruder, J.T.; Rapp, U.R.; Avruch, J. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature, 1993, 364(6435), 308-313.
[http://dx.doi.org/10.1038/364308a0] [PMID: 8332187]
[42]
Vojtek, A.B.; Hollenberg, S.M.; Cooper, J.A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell, 1993, 74(1), 205-214.
[http://dx.doi.org/10.1016/0092-8674(93)90307-C] [PMID: 8334704]
[43]
Kyriakis, J.M.; App, H.; Zhang, X.F.; Banerjee, P.; Brautigan, D.L.; Rapp, U.R.; Avruch, J. Raf-1 activates MAP kinase-kinase. Nature, 1992, 358(6385), 417-421.
[http://dx.doi.org/10.1038/358417a0] [PMID: 1322500]
[44]
Gallego, C.; Gupta, S.K.; Heasley, L.E.; Qian, N.X.; Johnson, G.L. Mitogen-activated protein kinase activation resulting from selective oncogene expression in NIH 3T3 and rat 1a cells. Proc. Natl. Acad. Sci. USA, 1992, 89(16), 7355-7359.
[http://dx.doi.org/10.1073/pnas.89.16.7355] [PMID: 1323832]
[45]
Wood, K.W.; Sarnecki, C.; Roberts, T.M.; Blenis, J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell, 1992, 68(6), 1041-1050.
[http://dx.doi.org/10.1016/0092-8674(92)90076-O] [PMID: 1312393]
[46]
Wennerberg, K.; Rossman, K.L.; Der, C.J. The Ras superfamily at a glance. J. Cell Sci., 2005, 118(Pt 5), 843-846.
[http://dx.doi.org/10.1242/jcs.01660] [PMID: 15731001]
[47]
Malaquias, A.C.; Jorge, A.A.L. Developmental syndromes of ras/mapk pathway dysregulation. eLS, , 2014. In Press
[48]
Urano, T.; Emkey, R.; Feig, L.A. Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. EMBO J., 1996, 15(4), 810-816.
[http://dx.doi.org/10.1002/j.1460-2075.1996.tb00416.x] [PMID: 8631302]
[49]
De Vos, A.M.; Tong, L.; Milburn, M. V; Matias, P.M.; Jancarik, J.; Noguchi, S.; Nishimura, S.; Miura, K.; Ohtsuka, E.; Kim, S.-H. Three-dimensional structure of an oncogene protein: catalytic domain of human c-h-ras p21. Science (80-. ), , 1988, 239, 888-893.
[50]
Pai, E.F.; Kabsch, W.; Krengel, U.; Holmes, K.C.; John, J.; Wittinghofer, A. Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation. Nature, 1989, 341(6239), 209-214.
[http://dx.doi.org/10.1038/341209a0] [PMID: 2476675]
[51]
Schlichting, I.; Almo, S.C.; Rapp, G.; Wilson, K.; Petratos, K.; Lentfer, A.; Wittinghofer, A.; Kabsch, W.; Pai, E.F.; Petsko, G.A.; Goody, R.S. Time-resolved X-ray crystallographic study of the conformational change in Ha-Ras p21 protein on GTP hydrolysis. Nature, 1990, 345(6273), 309-315.
[http://dx.doi.org/10.1038/345309a0] [PMID: 2111463]
[52]
Krengel, U.; Schlichting, I.; Scherer, A.; Schumann, R.; Frech, M.; John, J.; Kabsch, W.; Pai, E.F.; Wittinghofer, A. Three-dimensional structures of H-ras p21 mutants: molecular basis for their inability to function as signal switch molecules. Cell, 1990, 62(3), 539-548.
[http://dx.doi.org/10.1016/0092-8674(90)90018-A] [PMID: 2199064]
[53]
Tong, L.A.; de Vos, A.M.; Milburn, M.V.; Kim, S-H. Crystal structures at 2.2 A resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP. J. Mol. Biol., 1991, 217(3), 503-516.
[http://dx.doi.org/10.1016/0022-2836(91)90753-S] [PMID: 1899707]
[54]
Tong, L.; Milburn, M.V.; de Vos, A.M.; Kim, S.H. Structure of ras proteins. Science, 1989, 245, 244-244.
[http://dx.doi.org/10.1126/science.2665078]
[55]
Pai, E.F.; Krengel, U.; Petsko, G.A.; Goody, R.S.; Kabsch, W.; Wittinghofer, A. Refined crystal structure of the triphosphate conformation of H-ras p21 at 1.35 A resolution: implications for the mechanism of GTP hydrolysis. EMBO J., 1990, 9(8), 2351-2359.
[http://dx.doi.org/10.1002/j.1460-2075.1990.tb07409.x] [PMID: 2196171]
[56]
Milburn, M. V; Tong, L.; deVos, A.M.; Brünger, A.; Yamaizumi, Z.; Nishimura, S.; Kim, S.-H. Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science (80-. ),, 1990, 247, 939-945.
[57]
Scheffzek, K.; Lautwein, A.; Kabsch, W.; Ahmadian, M.R.; Wittinghofer, A. Crystal structure of the GTPase-activating domain of human p120GAP and implications for the interaction with Ras. Nature, 1996, 384(6609), 591-596.
[http://dx.doi.org/10.1038/384591a0] [PMID: 8955277]
[58]
Scheffzek, K.; Ahmadian, M.R.; Kabsch, W.; Wiesmüller, L.; Lautwein, A.; Schmitz, F.; Wittinghofer, A. The ras-rasgap complex: structural basis for gtpase activation and its loss in oncogenic ras mutants. Science (80-. ),, 1997, 277, 333-339.
[59]
Shih, T.Y.; Papageorge, A.G.; Stokes, P.E.; Weeks, M.O.; Scolnick, E.M. Guanine nucleotide-binding and autophosphorylating activities associated with the p21src protein of Harvey murine sarcoma virus. Nature, 1980, 287(5784), 686-691.
[http://dx.doi.org/10.1038/287686a0] [PMID: 6253810]
[60]
Stephen, A.G.; Esposito, D.; Bagni, R.K.; McCormick, F. Dragging ras back in the ring. Cancer Cell, 2014, 25(3), 272-281.
[http://dx.doi.org/10.1016/j.ccr.2014.02.017] [PMID: 24651010]
[61]
Bos, J.L.; Rehmann, H.; Wittinghofer, A. GEFs and GAPs: critical elements in the control of small G proteins. Cell, 2007, 129(5), 865-877.
[http://dx.doi.org/10.1016/j.cell.2007.05.018] [PMID: 17540168]
[62]
Hunter, J.C.; Manandhar, A.; Carrasco, M.A.; Gurbani, D.; Gondi, S.; Westover, K.D. Biochemical and structural analysis of common cancer-associated kras mutations. Mol. Cancer Res., 2015, 13(9), 1325-1335.
[http://dx.doi.org/10.1158/1541-7786.MCR-15-0203] [PMID: 26037647]
[63]
Hurley, J.B.; Simon, M.I.; Teplow, D.B.; Robishaw, J.D.; Gilman, A.G. Homologies between signal transducing g proteins and ras gene products. Science (80-. ),, 1984, 266, 860-862.
[64]
Bourne, H.R.; Sanders, D.A.; McCormick, F. The GTPase superfamily: conserved structure and molecular mechanism. Nature, 1991, 349(6305), 117-127.
[http://dx.doi.org/10.1038/349117a0] [PMID: 1898771]
[65]
Bos, J.L. ras oncogenes in human cancer: a review. Cancer Res., 1989, 49(17), 4682-4689.
[PMID: 2547513]
[66]
Scolnick, E.M.; Parks, W.P. Harvey sarcoma virus: a second murine type C sarcoma virus with rat genetic information. J. Virol., 1974, 13(6), 1211-1219.
[http://dx.doi.org/10.1128/JVI.13.6.1211-1219.1974] [PMID: 4364897]
[67]
Scolnick, E.M.; Rands, E.; Williams, D.; Parks, W.P. Studies on the nucleic acid sequences of Kirsten sarcoma virus: a model for formation of a mammalian RNA-containing sarcoma virus. J. Virol., 1973, 12(3), 458-463.
[http://dx.doi.org/10.1128/JVI.12.3.458-463.1973] [PMID: 4127029]
[68]
Anderson, G.R.; Robbins, K.C. Rat sequences of the Kirsten and Harvey murine sarcoma virus genomes: nature, origin, and expression in rat tumor RNA. J. Virol., 1976, 17(2), 335-351.
[http://dx.doi.org/10.1128/JVI.17.2.335-351.1976] [PMID: 176419]
[69]
Fukui, Y.; Kaziro, Y. Molecular cloning and sequence analysis of a ras gene from Schizosaccharomyces pombe. EMBO J., 1985, 4(3), 687-691.
[http://dx.doi.org/10.1002/j.1460-2075.1985.tb03684.x] [PMID: 4006903]
[70]
Fukui, Y.; Kozasa, T.; Kaziro, Y.; Takeda, T.; Yamamoto, M. Role of a ras homolog in the life cycle of Schizosaccharomyces pombe. Cell, 1986, 44(2), 329-336.
[http://dx.doi.org/10.1016/0092-8674(86)90767-1] [PMID: 3002633]
[71]
Spaargaren, M.; Bischoff, J.R. Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proc. Natl. Acad. Sci. USA, 1994, 91(26), 12609-12613.
[http://dx.doi.org/10.1073/pnas.91.26.12609] [PMID: 7809086]
[72]
Hofer, F.; Fields, S.; Schneider, C.; Martin, G.S. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proc. Natl. Acad. Sci. USA, 1994, 91(23), 11089-11093.
[http://dx.doi.org/10.1073/pnas.91.23.11089] [PMID: 7972015]
[73]
Kikuchi, A.; Demo, S.D.; Ye, Z.H.; Chen, Y.W.; Williams, L.T. ralGDS family members interact with the effector loop of ras p21. Mol. Cell. Biol., 1994, 14(11), 7483-7491.
[http://dx.doi.org/10.1128/MCB.14.11.7483] [PMID: 7935463]
[74]
Gutierrez, L.; Magee, A.I.; Marshall, C.J.; Hancock, J.F. Post-translational processing of p21ras is two-step and involves carboxyl-methylation and carboxy-terminal proteolysis. EMBO J., 1989, 8(4), 1093-1098.
[http://dx.doi.org/10.1002/j.1460-2075.1989.tb03478.x] [PMID: 2663468]
[75]
Deschenes, R.J.; Stimmel, J.B.; Clarke, S.; Stock, J.; Broach, J.R. RAS2 protein of Saccharomyces cerevisiae is methyl-esterified at its carboxyl terminus. J. Biol. Chem., 1989, 264(20), 11865-11873.
[PMID: 2663844]
[76]
Clarke, S.; Vogel, J.P.; Deschenes, R.J.; Posttranslational, S.J. Posttranslational modification of the ha-ras oncogene protein: evidence for a third class of protein carboxyl methyltransferases. Proc. Natl. Acad. Sci., 1988, 85, 7556-7556.
[77]
Gorfe, A.A.; Hanzal-Bayer, M.; Abankwa, D.; Hancock, J.F.; McCammon, J.A. Structure and dynamics of the full-length lipid-modified H-Ras protein in a 1,2-dimyristoylglycero-3-phosphocholine bilayer. J. Med. Chem., 2007, 50(4), 674-684.
[http://dx.doi.org/10.1021/jm061053f] [PMID: 17263520]
[78]
Hancock, J.F.; Parton, R.G. Ras plasma membrane signalling platforms. Biochem. J., 2005, 389, 1-11.
[79]
Rotblat, B.; Prior, I.A.; Muncke, C.; Parton, R.G.; Kloog, Y.; Henis, Y.I.; Hancock, J.F. Three separable domains regulate GTP-dependent association of H-ras with the plasma membrane. Mol. Cell. Biol., 2004, 24(15), 6799-6810.
[http://dx.doi.org/10.1128/MCB.24.15.6799-6810.2004] [PMID: 15254246]
[80]
Quan, Y.; Liu, G.; Yu, W.; Nie, Z.; Chen, J.; Lv, Z.; Zhang, Y. Expression, purification, and characterization of ras protein (bmras1) from bombyx mori. Comp. Funct. Genomics, 2012, 2012747539
[http://dx.doi.org/10.1155/2012/747539] [PMID: 22536118]
[81]
Fasano, O.; Aldrich, T.; Tamanoi, F.; Taparowsky, E.; Furth, M.; Wigler, M. Analysis of the transforming potential of the human H-ras gene by random mutagenesis. Proc. Natl. Acad. Sci. USA, 1984, 81(13), 4008-4012.
[http://dx.doi.org/10.1073/pnas.81.13.4008] [PMID: 6330729]
[82]
Hansen, M.; Rusyn, E.V.; Hughes, P.E.; Ginsberg, M.H.; Cox, A.D.; Willumsen, B.M. R-Ras C-terminal sequences are sufficient to confer R-Ras specificity to H-Ras. Oncogene, 2002, 21(28), 4448-4461.
[http://dx.doi.org/10.1038/sj.onc.1205538] [PMID: 12080475]
[83]
Chen, Z.; Otto, J.C.; Bergo, M.O.; Young, S.G.; Casey, P.J. The C-terminal polylysine region and methylation of K-Ras are critical for the interaction between K-Ras and microtubules. J. Biol. Chem., 2000, 275(52), 41251-41257.
[http://dx.doi.org/10.1074/jbc.M006687200] [PMID: 11007785]
[84]
Hart, K.C.; Donoghue, D.J. Derivatives of activated H-ras lacking C-terminal lipid modifications retain transforming ability if targeted to the correct subcellular location. Oncogene, 1997, 14(8), 945-953.
[http://dx.doi.org/10.1038/sj.onc.1200908] [PMID: 9050994]
[85]
Ahearn, I.; Zhou, M.; Philips, M.R. Posttranslational modifications of ras proteins. Cold Spring Harb. Perspect. Med., 2018, 8(11), 8.
[http://dx.doi.org/10.1101/cshperspect.a031484] [PMID: 29311131]
[86]
Choy, E.; Chiu, V.K.; Silletti, J.; Feoktistov, M.; Morimoto, T.; Michaelson, D.; Ivanov, I.E.; Philips, M.R. Endomembrane trafficking of ras: the CAAX motif targets proteins to the ER and Golgi. Cell, 1999, 98(1), 69-80.
[http://dx.doi.org/10.1016/S0092-8674(00)80607-8] [PMID: 10412982]
[87]
Cox, A.D.; Hisaka, M.M.; Buss, J.E.; Der, C.J. Specific isoprenoid modification is required for function of normal, but not oncogenic, Ras protein. Mol. Cell. Biol., 1992, 12(6), 2606-2615.
[http://dx.doi.org/10.1128/MCB.12.6.2606] [PMID: 1375323]
[88]
Abubaker, J.; Bavi, P.; Al-Haqawi, W.; Sultana, M.; Al-Harbi, S.; Al-Sanea, N.; Abduljabbar, A.; Ashari, L.H.; Alhomoud, S.; Al-Dayel, F.; Uddin, S.; Al-Kuraya, K.S. Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma. J. Pathol., 2009, 219(4), 435-445.
[http://dx.doi.org/10.1002/path.2625] [PMID: 19824059]
[89]
Zhang, X.; Cao, J.; Miller, S.P.; Jing, H.; Lin, H. Comparative nucleotide-dependent interactome analysis reveals shared and differential properties of kras4a and kras4b. ACS Cent. Sci., 2018, 4(1), 71-80.
[http://dx.doi.org/10.1021/acscentsci.7b00440] [PMID: 29392178]
[90]
Nussinov, R.; Tsai, C-J.; Chakrabarti, M.; Jang, H. A new view of ras isoforms in cancers. Cancer Res., 2016, 76(1), 18-23.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-1536] [PMID: 26659836]
[91]
Tsai, F.D.; Lopes, M.S.; Zhou, M.; Court, H.; Ponce, O.; Fiordalisi, J.J.; Gierut, J.J.; Cox, A.D.; Haigis, K.M.; Philips, M.R. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proc. Natl. Acad. Sci. USA, 2015, 112(3), 779-784.
[http://dx.doi.org/10.1073/pnas.1412811112] [PMID: 25561545]
[92]
Casique-Aguirre, D.; Briseño-Díaz, P.; García-Gutiérrez, P.; la Rosa, C.H.G.; Quintero-Barceinas, R.S.; Rojo-Domínguez, A.; Vergara, I.; Medina, L.A.; Correa-Basurto, J.; Bello, M.; Hernández-Rivas, R. Del RocioThompson-Bonilla, M.; Vargas, M. KRas4B-PDE6δ complex stabilization by small molecules obtained by virtual screening affects Ras signaling in pancreatic cancer. BMC Cancer, 2018, 18(1), 1299.
[http://dx.doi.org/10.1186/s12885-018-5142-7] [PMID: 30594165]
[93]
Fiordalisi, J.J.; Johnson, R.L., II; Weinbaum, C.A.; Sakabe, K.; Chen, Z.; Casey, P.J.; Cox, A.D. High affinity for farnesyltransferase and alternative prenylation contribute individually to K-Ras4B resistance to farnesyltransferase inhibitors. J. Biol. Chem., 2003, 278(43), 41718-41727.
[http://dx.doi.org/10.1074/jbc.M305733200] [PMID: 12882980]
[94]
Casey, P.J.; Solski, P.A.; Der, C.J.; Buss, J.E. p21ras is modified by a farnesyl isoprenoid. Proc. Natl. Acad. Sci. USA, 1989, 86(21), 8323-8327.
[http://dx.doi.org/10.1073/pnas.86.21.8323] [PMID: 2682646]
[95]
Willumsen, B.M.; Christensen, A.; Hubbert, N.L.; Papageorge, A.G.; Lowy, D.R. The p21 ras C-terminus is required for transformation and membrane association. Nature, 1984, 310(5978), 583-586.
[http://dx.doi.org/10.1038/310583a0] [PMID: 6087162]
[96]
Spoerner, M.; Herrmann, C.; Vetter, I.R.; Kalbitzer, H.R.; Wittinghofer, A. Dynamic properties of the Ras switch I region and its importance for binding to effectors. Proc. Natl. Acad. Sci. USA, 2001, 98(9), 4944-4949.
[http://dx.doi.org/10.1073/pnas.081441398] [PMID: 11320243]
[97]
Quilliam, L.A.; Hisaka, M.M.; Zhong, S.; Lowry, A.; Mosteller, R.D.; Han, J.; Drugan, J.K.; Broek, D.; Campbell, S.L.; Der, C.J. Involvement of the switch 2 domain of Ras in its interaction with guanine nucleotide exchange factors. J. Biol. Chem., 1996, 271(19), 11076-11082.
[http://dx.doi.org/10.1074/jbc.271.19.11076] [PMID: 8626650]
[98]
Shimizu, H.; Toma-Fukai, S.; Kontani, K.; Katada, T.; Shimizu, T. GEF mechanism revealed by the structure of SmgGDS-558 and farnesylated RhoA complex and its implication for a chaperone mechanism. Proc. Natl. Acad. Sci. USA, 2018, 115(38), 9563-9568.
[http://dx.doi.org/10.1073/pnas.1804740115] [PMID: 30190425]
[99]
Toma-Fukai, S.; Shimizu, T. Structural Insights into the Regulation Mechanism of Small GTPases by GEFs. Molecules, 2019, 24(18), 3308.
[http://dx.doi.org/10.3390/molecules24183308] [PMID: 31514408]
[100]
Cherfils, J.; Zeghouf, M. Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol. Rev., 2013, 93(1), 269-309.
[http://dx.doi.org/10.1152/physrev.00003.2012] [PMID: 23303910]
[101]
Ledford, H. Cancer: The Ras renaissance. Nature, 2015, 520(7547), 278-280.
[http://dx.doi.org/10.1038/520278a] [PMID: 25877186]
[102]
Hobbs, G.A.; Der, C.J.; Rossman, K.L. RAS isoforms and mutations in cancer at a glance. J. Cell Sci., 2016, 129(7), 1287-1292.
[http://dx.doi.org/10.1242/jcs.182873] [PMID: 26985062]
[103]
Sánchez-Muñoz, A.; Gallego, E.; de Luque, V.; Pérez-Rivas, L.G.; Vicioso, L.; Ribelles, N.; Lozano, J.; Alba, E. Lack of evidence for KRAS oncogenic mutations in triple-negative breast cancer. BMC Cancer, 2010, 10, 136.
[http://dx.doi.org/10.1186/1471-2407-10-136] [PMID: 20385028]
[104]
Sanaei, S.; Hashemi, M.; Eskandari, E.; Hashemi, S.M.; Bahari, G. KRAS gene polymorphisms and their impact on breast cancer risk in an iranian population. Asian Pac. J. Cancer Prev., 2017, 18(5), 1301-1305.
[PMID: 28610418]
[105]
Kim, R-K.; Suh, Y.; Yoo, K-C.; Cui, Y-H.; Kim, H.; Kim, M-J.; Gyu Kim, I.; Lee, S-J. Activation of KRAS promotes the mesenchymal features of basal-type breast cancer. Exp. Mol. Med., 2015, 47e137
[http://dx.doi.org/10.1038/emm.2014.99] [PMID: 25633745]
[106]
Galiè, M. RAS as supporting actor in breast cancer. Front. Oncol., 2019, 9, 1199.
[http://dx.doi.org/10.3389/fonc.2019.01199] [PMID: 31781501]
[107]
di Magliano, M.P.; Logsdon, C.D. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology, 2013, 144(6), 1220-1229.
[http://dx.doi.org/10.1053/j.gastro.2013.01.071] [PMID: 23622131]
[108]
Collins, M.A.; Brisset, J-C.; Zhang, Y.; Bednar, F.; Pierre, J.; Heist, K.A.; Galbán, C.J.; Galbán, S.; di Magliano, M.P. Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PLoS One, 2012, 7(12)e49707
[http://dx.doi.org/10.1371/journal.pone.0049707] [PMID: 23226501]
[109]
Buscail, L.; Bournet, B.; Cordelier, P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol., 2020, 17(3), 153-168.
[http://dx.doi.org/10.1038/s41575-019-0245-4] [PMID: 32005945]
[110]
Porru, M.; Pompili, L.; Caruso, C.; Biroccio, A.; Leonetti, C. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J. Exp. Clin. Cancer Res., 2018, 37(1), 57.
[http://dx.doi.org/10.1186/s13046-018-0719-1] [PMID: 29534749]
[111]
Bos, J.L.; Fearon, E.R.; Hamilton, S.R.; Verlaan-de Vries, M.; van Boom, J.H.; van der Eb, A.J.; Vogelstein, B. Prevalence of ras gene mutations in human colorectal cancers. Nature, 1987, 327(6120), 293-297.
[http://dx.doi.org/10.1038/327293a0] [PMID: 3587348]
[112]
Forrester, K.; Almoguera, C.; Han, K.; Grizzle, W.E.; Perucho, M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature, 1987, 327(6120), 298-303.
[http://dx.doi.org/10.1038/327298a0] [PMID: 2438556]
[113]
Westcott, P.M.K.; To, M.D. The genetics and biology of KRAS in lung cancer. Chin. J. Cancer, 2013, 32(2), 63-70.
[http://dx.doi.org/10.5732/cjc.012.10098] [PMID: 22776234]
[114]
Román, M.; Baraibar, I.; López, I.; Nadal, E.; Rolfo, C.; Vicent, S.; Gil-Bazo, I. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol. Cancer, 2018, 17(1), 33.
[http://dx.doi.org/10.1186/s12943-018-0789-x] [PMID: 29455666]
[115]
Ambrogio, C.; Nadal, E.; Villanueva, A.; Gómez-López, G.; Cash, T.P.; Barbacid, M.; Santamaría, D. KRAS-driven lung adenocarcinoma: combined DDR1/Notch inhibition as an effective therapy. ESMO Open, 2016, 1(5)e000076
[http://dx.doi.org/10.1136/esmoopen-2016-000076] [PMID: 27843638]
[116]
Guerrero, I.; Calzada, P.; Mayer, A.; Pellicer, A. A molecular approach to leukemogenesis: mouse lymphomas contain an activated c-ras oncogene. Proc. Natl. Acad. Sci. USA, 1984, 81(1), 202-205.
[http://dx.doi.org/10.1073/pnas.81.1.202] [PMID: 6582476]
[117]
Balmain, A.; Pragnell, I.B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature, 1983, 303(5912), 72-74.
[http://dx.doi.org/10.1038/303072a0] [PMID: 6843661]
[118]
Sukumar, S.; Notario, V.; Martin-Zanca, D.; Barbacid, M. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations. Nature, 1983, 306(5944), 658-661.
[http://dx.doi.org/10.1038/306658a0] [PMID: 6318112]
[119]
Weinberg, R.A. The discovery of ras and its biological importance BT.GTPases in Biology; Dickey, B.F.; Birnbaumer, L., Eds.; Springer Berlin Heidelberg: Berlin, Heidelberg, 1993, pp. 249-258.
[http://dx.doi.org/10.1007/978-3-642-78267-1_17]
[120]
Murugan, A.K.; Grieco, M.; Tsuchida, N. RAS mutations in human cancers: Roles in precision medicine. Semin. Cancer Biol., 2019, 59, 23-35.
[http://dx.doi.org/10.1016/j.semcancer.2019.06.007] [PMID: 31255772]
[121]
Cox, A.D.; Der, C.J. Ras history: The saga continues. Small GTPases, 2010, 1(1), 2-27.
[http://dx.doi.org/10.4161/sgtp.1.1.12178] [PMID: 21686117]
[122]
Prior, I.A.; Lewis, P.D.; Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res., 2012, 72(10), 2457-2467.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-2612] [PMID: 22589270]
[123]
Kodaz, H.; Kostek, O.; Hacioglu, M.B. Bulent Erdogan; Kodaz, C.E.; Hacibekiroglu, I.; Turkmen, E.; Uzunoglu, S.; Cicin, I. Frequency of ras mutations (kras, nras, hras) in human solid cancer. EURASIAN J. Med. Oncol., 2017, 1, 1-7.
[124]
Jones, R.P.; Sutton, P.A.; Evans, J.P.; Clifford, R.; McAvoy, A.; Lewis, J.; Rousseau, A.; Mountford, R.; McWhirter, D.; Malik, H.Z. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br. J. Cancer, 2017, 116(7), 923-929.
[http://dx.doi.org/10.1038/bjc.2017.37] [PMID: 28208157]
[125]
Ferrer, I.; Zugazagoitia, J.; Herbertz, S.; John, W.; Paz-Ares, L.; Schmid-Bindert, G. KRAS-Mutant non-small cell lung cancer: From biology to therapy. Lung Cancer, 2018, 124, 53-64.
[http://dx.doi.org/10.1016/j.lungcan.2018.07.013] [PMID: 30268480]
[126]
Nussinov, R.; Jang, H.; Tsai, C-J.; Cheng, F. Correction: Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers. PLOS Comput. Biol., 2019, 15(6)e1007114
[http://dx.doi.org/10.1371/journal.pcbi.1007114] [PMID: 31188819]
[127]
Malhotra, S.; Alsulami, A.F.; Heiyun, Y.; Ochoa, B.M.; Jubb, H.; Forbes, S.; Blundell, T.L. Understanding the impacts of missense mutations on structures and functions of human cancer-related genes: A preliminary computational analysis of the COSMIC Cancer Gene Census. PLoS One, 2019, 14(7)e0219935
[http://dx.doi.org/10.1371/journal.pone.0219935] [PMID: 31323058]
[128]
Rajasekharan, S.K.; Raman, T. Ras and ras mutations in cancer. Cent. Eur. J. Biol., 2013, 8, 609-624.
[129]
Smit, V.T.; Boot, A.J.; Smits, A.M.; Fleuren, G.J.; Cornelisse, C.J.; Bos, J.L. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res., 1988, 16(16), 7773-7782.
[http://dx.doi.org/10.1093/nar/16.16.7773] [PMID: 3047672]
[130]
Graziano, S.L.; Gamble, G.P.; Newman, N.B.; Abbott, L.Z.; Rooney, M.; Mookherjee, S.; Lamb, M.L.; Kohman, L.J.; Poiesz, B.J. Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer. J. Clin. Oncol., 1999, 17(2), 668-675.
[http://dx.doi.org/10.1200/JCO.1999.17.2.668] [PMID: 10080613]
[131]
Serebriiskii, I.G.; Connelly, C.; Frampton, G.; Newberg, J.; Cooke, M.; Miller, V.; Ali, S.; Ross, J.S.; Handorf, E.; Arora, S.; Lieu, C.; Golemis, E.A.; Meyer, J.E. Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients. Nat. Commun., 2019, 10(1), 3722.
[http://dx.doi.org/10.1038/s41467-019-11530-0] [PMID: 31427573]
[132]
Knijn, N.; van de Water, C.; van Vliet, S.; Meijer, J.; Riemersma, S.; Tebar, M.; Punt, C.; Mekenkamp, L.; Simmer, F.; Nagtegaal, I. Sequencing of ras/raf pathway genes in primary colorectal cancer and matched liver and lung metastases. Appl. Cancer Res., 2019, 39, 9.
[http://dx.doi.org/10.1186/s41241-019-0079-y]
[133]
Yang, H.; Liang, S-Q.; Schmid, R.A.; Peng, R-W. New horizons in kras-mutant lung cancer: dawn after darkness. Front. Oncol., 2019, 9, 953.
[http://dx.doi.org/10.3389/fonc.2019.00953] [PMID: 31612108]
[134]
Li, S.; Balmain, A.; Counter, C.M. A model for RAS mutation patterns in cancers: finding the sweet spot. Nat. Rev. Cancer, 2018, 18(12), 767-777.
[http://dx.doi.org/10.1038/s41568-018-0076-6] [PMID: 30420765]
[135]
Haigis, K.M. KRAS alleles: the devil is in the detail. Trends Cancer, 2017, 3(10), 686-697.
[http://dx.doi.org/10.1016/j.trecan.2017.08.006] [PMID: 28958387]
[136]
Kramer, Ij. Chapter 11 - Signal transduction to and from adhesion molecules. InSignal Transduction. (Third Edition), 3rd ed; Academic Press: Boston, 2016, pp. 655-702.
[137]
Hesketh, R. Ras gene family. InEncyclopedia of Genetics; Academic Press: New York, 2001, pp. 1602-1607.
[138]
Basson, M.A. Signaling in cell differentiation and morphogenesis. Cold Spring Harb. Perspect. Biol., 2012, 4(6)a008151
[http://dx.doi.org/10.1101/cshperspect.a008151] [PMID: 22570373]
[139]
Rajalingam, K.; Schreck, R.; Rapp, U.R.; Albert, S. Ras oncogenes and their downstream targets. Biochim. Biophys. Acta, 2007, 1773(8), 1177-1195.
[http://dx.doi.org/10.1016/j.bbamcr.2007.01.012] [PMID: 17428555]
[140]
Missero, C.; Pirro, M.T.; Di Lauro, R. Multiple ras downstream pathways mediate functional repression of the homeobox gene product TTF-1. Mol. Cell. Biol., 2000, 20(8), 2783-2793.
[http://dx.doi.org/10.1128/MCB.20.8.2783-2793.2000] [PMID: 10733581]
[141]
Margolis, B.; Skolnik, E.Y. Activation of Ras by receptor tyrosine kinases. J. Am. Soc. Nephrol., 1994, 5(6), 1288-1299.
[PMID: 7893993]
[142]
Ahmed, Z.; Timsah, Z.; Suen, K.M.; Cook, N.P.; Lee, G.R., IV; Lin, C-C.; Gagea, M.; Marti, A.A.; Ladbury, J.E. Grb2 monomer-dimer equilibrium determines normal versus oncogenic function. Nat. Commun., 2015, 6, 7354.
[http://dx.doi.org/10.1038/ncomms8354] [PMID: 26103942]
[143]
Belov, A.A.; Mohammadi, M. Grb2, a double-edged sword of receptor tyrosine kinase signaling. Sci. Signal., 2012, 5(249), pe49.
[http://dx.doi.org/10.1126/scisignal.2003576] [PMID: 23131845]
[144]
Zarich, N.; Oliva, J.L.; Martínez, N.; Jorge, R.; Ballester, A.; Gutiérrez-Eisman, S.; García-Vargas, S.; Rojas, J.M. Grb2 is a negative modulator of the intrinsic Ras-GEF activity of hSos1. Mol. Biol. Cell, 2006, 17(8), 3591-3597.
[http://dx.doi.org/10.1091/mbc.e05-12-1104] [PMID: 16760435]
[145]
Chang, F.; Steelman, L.S.; Lee, J.T.; Shelton, J.G.; Navolanic, P.M.; Blalock, W.L.; Franklin, R.A.; McCubrey, J.A. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia, 2003, 17(7), 1263-1293.
[http://dx.doi.org/10.1038/sj.leu.2402945] [PMID: 12835716]
[146]
Castellano, E.; Downward, J. RAS interaction with pi3k: more than just another effector pathway. Genes Cancer, 2011, 2(3), 261-274.
[http://dx.doi.org/10.1177/1947601911408079] [PMID: 21779497]
[147]
Yang, S.; Liu, G. Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma. Oncol. Lett., 2017, 13(3), 1041-1047.
[http://dx.doi.org/10.3892/ol.2017.5557] [PMID: 28454211]
[148]
McCubrey, J.A.; Steelman, L.S.; Chappell, W.H.; Abrams, S.L.; Wong, E.W.T.; Chang, F.; Lehmann, B.; Terrian, D.M.; Milella, M.; Tafuri, A.; Stivala, F.; Libra, M.; Basecke, J.; Evangelisti, C.; Martelli, A.M.; Franklin, R.A. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta, 2007, 1773(8), 1263-1284.
[http://dx.doi.org/10.1016/j.bbamcr.2006.10.001] [PMID: 17126425]
[149]
Su, H.; McClarty, G.; Dong, F.; Hatch, G.M.; Pan, Z.K.; Zhong, G. Activation of Raf/MEK/ERK/cPLA2 signaling pathway is essential for chlamydial acquisition of host glycerophospholipids. J. Biol. Chem., 2004, 279(10), 9409-9416.
[http://dx.doi.org/10.1074/jbc.M312008200] [PMID: 14676189]
[150]
Ge, C.; Xiao, G.; Jiang, D.; Yang, Q.; Hatch, N.E.; Roca, H.; Franceschi, R.T. Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J. Biol. Chem., 2009, 284(47), 32533-32543.
[http://dx.doi.org/10.1074/jbc.M109.040980] [PMID: 19801668]
[151]
Pagon, Z.; Volker, J.; Cooper, G.M.; Hansen, U. Mammalian transcription factor LSF is a target of ERK signaling. J. Cell. Biochem., 2003, 89(4), 733-746.
[http://dx.doi.org/10.1002/jcb.10549] [PMID: 12858339]
[152]
Cruzalegui, F.H.; Cano, E.; Treisman, R. ERK activation induces phosphorylation of Elk-1 at multiple S/T-P motifs to high stoichiometry. Oncogene, 1999, 18(56), 7948-7957.
[http://dx.doi.org/10.1038/sj.onc.1203362] [PMID: 10637505]
[153]
Liu, P.; Wang, Y.; Li, X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm. Sin. B, 2019, 9(5), 871-879.
[http://dx.doi.org/10.1016/j.apsb.2019.03.002] [PMID: 31649840]
[154]
Lu, S.; Jang, H.; Nussinov, R.; Zhang, J. The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B. Sci. Rep., 2016, 6, 21949.
[http://dx.doi.org/10.1038/srep21949] [PMID: 26902995]
[155]
Mörchen, B.; Shkura, O.; Stoll, R.; Helfrich, I. Targeting the “undruggable” ras - new strategies - new hope? Cancer Drug Resist., 2019, 2, 813-826.
[http://dx.doi.org/10.20517/cdr.2019.21]
[156]
Rowinsky, E.K.; Windle, J.J.; Von Hoff, D.D. Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J. Clin. Oncol., 1999, 17(11), 3631-3652.
[http://dx.doi.org/10.1200/JCO.1999.17.11.3631] [PMID: 10550163]
[157]
Vogt, A.; Qian, Y.; Blaskovich, M.A.; Fossum, R.D.; Hamilton, A.D.; Sebti, S.M. A non-peptide mimetic of Ras-CAAX: selective inhibition of farnesyltransferase and Ras processing. J. Biol. Chem., 1995, 270(2), 660-664.
[http://dx.doi.org/10.1074/jbc.270.2.660] [PMID: 7822292]
[158]
Appels, N.M.G.M.; Beijnen, J.H.; Schellens, J.H.M. Development of farnesyl transferase inhibitors: a review. Oncologist, 2005, 10(8), 565-578.
[http://dx.doi.org/10.1634/theoncologist.10-8-565] [PMID: 16177281]
[159]
Head, J.; Johnston, S.R.D. New targets for therapy in breast cancer: farnesyltransferase inhibitors. Breast Cancer Res., 2004, 6(6), 262-268.
[http://dx.doi.org/10.1186/bcr947] [PMID: 15535857]
[160]
Wang, J.; Yao, X.; Huang, J. New tricks for human farnesyltransferase inhibitor: cancer and beyond. MedChemComm, 2017, 8(5), 841-854.
[http://dx.doi.org/10.1039/C7MD00030H] [PMID: 30108801]
[161]
Kazi, A.; Xiang, S.; Yang, H.; Chen, L.; Kennedy, P.; Ayaz, M.; Fletcher, S.; Cummings, C.; Lawrence, H.R.; Beato, F.; Kang, Y.; Kim, M.P.; Delitto, A.; Underwood, P.W.; Fleming, J.B.; Trevino, J.G.; Hamilton, A.D.; Sebti, S.M. Dual farnesyl and geranylgeranyl transferase inhibitor thwarts mutant kras-driven patient-derived pancreatic tumors. Clin. Cancer Res., 2019, 25(19), 5984-5996.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-3399] [PMID: 31227505]
[162]
Berndt, N.; Hamilton, A.D.; Sebti, S.M. Targeting protein prenylation for cancer therapy. Nat. Rev. Cancer, 2011, 11(11), 775-791.
[http://dx.doi.org/10.1038/nrc3151] [PMID: 22020205]
[163]
Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer, 2003, 3(1), 11-22.
[http://dx.doi.org/10.1038/nrc969] [PMID: 12509763]
[164]
Schmick, M.; Vartak, N.; Papke, B.; Kovacevic, M.; Truxius, D.C.; Rossmannek, L.; Bastiaens, P.I.H. KRas localizes to the plasma membrane by spatial cycles of solubilization, trapping and vesicular transport. Cell, 2014, 157(2), 459-471.
[http://dx.doi.org/10.1016/j.cell.2014.02.051] [PMID: 24725411]
[165]
Chandra, A.; Grecco, H.E.; Pisupati, V.; Perera, D.; Cassidy, L.; Skoulidis, F.; Ismail, S.A.; Hedberg, C.; Hanzal-Bayer, M.; Venkitaraman, A.R.; Wittinghofer, A.; Bastiaens, P.I.H. The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins. Nat. Cell Biol., 2011, 14(2), 148-158.
[http://dx.doi.org/10.1038/ncb2394] [PMID: 22179043]
[166]
Colombo, S.; Peri, F.; Tisi, R.; Nicotra, F.; Martegani, E. Design and characterization of a new class of inhibitors of ras activation. Ann. N. Y. Acad. Sci., 2004, 1030, 52-61.
[http://dx.doi.org/10.1196/annals.1329.007] [PMID: 15659780]
[167]
Taveras, A.G.; Remiszewski, S.W.; Doll, R.J.; Cesarz, D.; Huang, E.C.; Kirschmeier, P.; Pramanik, B.N.; Snow, M.E.; Wang, Y-S.; del Rosario, J.D.; Vibulbhan, B.; Bauer, B.B.; Brown, J.E.; Carr, D.; Catino, J.; Evans, C.A.; Girijavallabhan, V.; Heimark, L.; James, L.; Liberles, S.; Nash, C.; Perkins, L.; Senior, M.M.; Tsarbopoulos, A.; Webber, S.E.; Aust, R.; Brown, E.; Delisle, D.; Fuhrman, S.; Hendrickson, T.; Kissinger, C.; Love, R.; Sisson, W.; Villafranca, E.; Webber, S.E. Ras oncoprotein inhibitors: the discovery of potent, ras nucleotide exchange inhibitors and the structural determination of a drug-protein complex. Bioorg. Med. Chem., 1997, 5(1), 125-133.
[http://dx.doi.org/10.1016/S0968-0896(96)00202-7] [PMID: 9043664]
[168]
Ganguly, A.K.; Wang, Y-S.; Pramanik, B.N.; Doll, R.J.; Snow, M.E.; Taveras, A.G.; Remiszewski, S.; Cesarz, D.; del Rosario, J.; Vibulbhan, B.; Brown, J.E.; Kirschmeier, P.; Huang, E.C.; Heimark, L.; Tsarbopoulos, A.; Girijavallabhan, V.M.; Aust, R.M.; Brown, E.L.; DeLisle, D.M.; Fuhrman, S.A.; Hendrickson, T.F.; Kissinger, C.R.; Love, R.A.; Sisson, W.A.; Webber, S.E.; Webber, S.E. Interaction of a novel GDP exchange inhibitor with the Ras protein. Biochemistry, 1998, 37(45), 15631-15637.
[http://dx.doi.org/10.1021/bi9805691] [PMID: 9843367]
[169]
Zhang, Z.; Tang, W. Drug metabolism in drug discovery and development. Acta Pharm. Sin. B, 2018, 8(5), 721-732.
[http://dx.doi.org/10.1016/j.apsb.2018.04.003] [PMID: 30245961]
[170]
Ashani, Y.; Silman, I. Hydroxylamines and oximes: biological properties and potential uses as therapeutic agents.PATAI’S Chemistry of Functional Groups; Wiley and Sons: Hoboken, 2010.
[171]
Waldmann, H.; Karaguni, I-M.; Carpintero, M.; Gourzoulidou, E.; Herrmann, C.; Brockmann, C.; Oschkinat, H.; Müller, O. Sulindac-derived Ras pathway inhibitors target the Ras-Raf interaction and downstream effectors in the Ras pathway. Angew. Chem. Int. Ed. Engl., 2004, 43(4), 454-458.
[http://dx.doi.org/10.1002/anie.200353089] [PMID: 14735533]
[172]
Karaguni, I-M.; Herter, P.; Debruyne, P.; Chtarbova, S.; Kasprzynski, A.; Herbrand, U.; Ahmadian, M-R.; Glüsenkamp, K-H.; Winde, G.; Mareel, M.; Möröy, T.; Müller, O. The new sulindac derivative IND 12 reverses Ras-induced cell transformation. Cancer Res., 2002, 62(6), 1718-1723.
[PMID: 11912145]
[173]
Cruz-Migoni, A.; Canning, P.; Quevedo, C.E.; Bataille, C.J.R.; Bery, N.; Miller, A.; Russell, A.J.; Phillips, S.E.V.; Carr, S.B.; Rabbitts, T.H. Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds. Proc. Natl. Acad. Sci. USA, 2019, 116(7), 2545-2550.
[http://dx.doi.org/10.1073/pnas.1811360116] [PMID: 30683716]
[174]
Maurer, T.; Garrenton, L.S.; Oh, A.; Pitts, K.; Anderson, D.J.; Skelton, N.J.; Fauber, B.P.; Pan, B.; Malek, S.; Stokoe, D.; Ludlam, M.J.C.; Bowman, K.K.; Wu, J.; Giannetti, A.M.; Starovasnik, M.A.; Mellman, I.; Jackson, P.K.; Rudolph, J.; Wang, W.; Fang, G. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc. Natl. Acad. Sci. USA, 2012, 109(14), 5299-5304.
[http://dx.doi.org/10.1073/pnas.1116510109] [PMID: 22431598]
[175]
Yan, C.; Jones, D.N.M.; Theodorescu, D. Drugging the Ral GTPase. Small GTPases, 2015, 6(3), 157-159.
[http://dx.doi.org/10.1080/21541248.2015.1018403] [PMID: 26280620]
[176]
Peyssonnaux, C.; Eychène, A. The Raf/MEK/ERK pathway: new concepts of activation. Biol. Cell, 2001, 93(1-2), 53-62.
[http://dx.doi.org/10.1016/S0248-4900(01)01125-X] [PMID: 11730323]
[177]
Howe, L.R.; Leevers, S.J.; Gómez, N.; Nakielny, S.; Cohen, P.; Marshall, C.J. Activation of the MAP kinase pathway by the protein kinase raf. Cell, 1992, 71(2), 335-342.
[http://dx.doi.org/10.1016/0092-8674(92)90361-F] [PMID: 1330321]
[178]
Pearson, G.; Robinson, F.; Beers Gibson, T.; Xu, B.E.; Karandikar, M.; Berman, K.; Cobb, M.H. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev., 2001, 22(2), 153-183.
[PMID: 11294822]
[179]
Durrant, D.E.; Morrison, D.K. Targeting the Raf kinases in human cancer: the Raf dimer dilemma. Br. J. Cancer, 2018, 118(1), 3-8.
[http://dx.doi.org/10.1038/bjc.2017.399] [PMID: 29235562]
[180]
Cheng, Y.; Tian, H. Current Development Status of MEK Inhibitors. Molecules, 2017, 22(10), 1551.
[http://dx.doi.org/10.3390/molecules22101551] [PMID: 28954413]
[181]
Cox, A.D.; Der, C.J. The RAF inhibitor paradox revisited. Cancer Cell, 2012, 21(2), 147-149.
[http://dx.doi.org/10.1016/j.ccr.2012.01.017] [PMID: 22340588]
[182]
Liu, F.; Yang, X.; Geng, M.; Huang, M. Targeting ERK, an Achilles’ Heel of the MAPK pathway, in cancer therapy. Acta Pharm. Sin. B, 2018, 8(4), 552-562.
[http://dx.doi.org/10.1016/j.apsb.2018.01.008] [PMID: 30109180]
[183]
Banks, M.; Crowell, K.; Proctor, A.; Jensen, B.C. Cardiovascular effects of the mek inhibitor, trametinib: a case report, literature review, and consideration of mechanism. Cardiovasc. Toxicol., 2017, 17(4), 487-493.
[http://dx.doi.org/10.1007/s12012-017-9425-z] [PMID: 28861837]
[184]
Fields, J.; Cisneros, I.E.; Borgmann, K.; Ghorpade, A. Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression. PLoS One, 2013, 8(2)e56891
[http://dx.doi.org/10.1371/journal.pone.0056891] [PMID: 23457635]
[185]
Nagaria, T.S.; Shi, C.; Leduc, C.; Hoskin, V.; Sikdar, S.; Sangrar, W.; Greer, P.A. Combined targeting of Raf and Mek synergistically inhibits tumorigenesis in triple negative breast cancer model systems. Oncotarget, 2017, 8(46), 80804-80819.
[http://dx.doi.org/10.18632/oncotarget.20534] [PMID: 29113345]
[186]
Shima, F.; Yoshikawa, Y.; Ye, M.; Araki, M.; Matsumoto, S.; Liao, J.; Hu, L.; Sugimoto, T.; Ijiri, Y.; Takeda, A.; Nishiyama, Y.; Sato, C.; Muraoka, S.; Tamura, A.; Osoda, T.; Tsuda, K.; Miyakawa, T.; Fukunishi, H.; Shimada, J.; Kumasaka, T.; Yamamoto, M.; Kataoka, T. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proc. Natl. Acad. Sci. USA, 2013, 110(20), 8182-8187.
[http://dx.doi.org/10.1073/pnas.1217730110] [PMID: 23630290]
[187]
Keeton, A.B.; Salter, E.A.; Piazza, G.A. The RAS-Effector Interaction as a Drug Target. Cancer Res., 2017, 77(2), 221-226.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0938] [PMID: 28062402]
[188]
Han, C.W.; Jeong, M.S.; Jang, S.B. Structure, signaling and the drug discovery of the Ras oncogene protein. BMB Rep., 2017, 50(7), 355-360.
[http://dx.doi.org/10.5483/BMBRep.2017.50.7.062] [PMID: 28571593]
[189]
Engelman, J.A.; Luo, J.; Cantley, L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet., 2006, 7(8), 606-619.
[http://dx.doi.org/10.1038/nrg1879] [PMID: 16847462]
[190]
Katso, R.; Okkenhaug, K.; Ahmadi, K.; White, S.; Timms, J.; Waterfield, M.D. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol., 2001, 17, 615-675.
[http://dx.doi.org/10.1146/annurev.cellbio.17.1.615] [PMID: 11687500]
[191]
Martini, M.; De Santis, M.C.; Braccini, L.; Gulluni, F.; Hirsch, E. PI3K/AKT signaling pathway and cancer: an updated review. Ann. Med., 2014, 46(6), 372-383.
[http://dx.doi.org/10.3109/07853890.2014.912836] [PMID: 24897931]
[192]
Yang, J.; Nie, J.; Ma, X.; Wei, Y.; Peng, Y.; Wei, X. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol. Cancer, 2019, 18(1), 26.
[http://dx.doi.org/10.1186/s12943-019-0954-x] [PMID: 30782187]
[193]
Yuan, T.L.; Cantley, L.C. PI3K pathway alterations in cancer: variations on a theme. Oncogene, 2008, 27(41), 5497-5510.
[http://dx.doi.org/10.1038/onc.2008.245] [PMID: 18794884]
[194]
Rodriguez-Viciana, P.; Warne, P.H.; Khwaja, A.; Marte, B.M.; Pappin, D.; Das, P.; Waterfield, M.D.; Ridley, A.; Downward, J. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell, 1997, 89(3), 457-467.
[http://dx.doi.org/10.1016/S0092-8674(00)80226-3] [PMID: 9150145]
[195]
Pacold, M.E.; Suire, S.; Perisic, O.; Lara-Gonzalez, S.; Davis, C.T.; Walker, E.H.; Hawkins, P.T.; Stephens, L.; Eccleston, J.F.; Williams, R.L. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase γ. Cell, 2000, 103(6), 931-943.
[http://dx.doi.org/10.1016/S0092-8674(00)00196-3] [PMID: 11136978]
[196]
Wong, K-K.; Engelman, J.A.; Cantley, L.C. Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev., 2010, 20(1), 87-90.
[http://dx.doi.org/10.1016/j.gde.2009.11.002] [PMID: 20006486]
[197]
Hennessy, B.T.; Smith, D.L.; Ram, P.T.; Lu, Y.; Mills, G.B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov., 2005, 4(12), 988-1004.
[http://dx.doi.org/10.1038/nrd1902] [PMID: 16341064]
[198]
Barault, L.; Veyrie, N.; Jooste, V.; Lecorre, D.; Chapusot, C.; Ferraz, J-M.; Lièvre, A.; Cortet, M.; Bouvier, A-M.; Rat, P.; Roignot, P.; Faivre, J.; Laurent-Puig, P.; Piard, F. Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int. J. Cancer, 2008, 122(10), 2255-2259.
[http://dx.doi.org/10.1002/ijc.23388] [PMID: 18224685]
[199]
Ollikainen, M.; Gylling, A.; Puputti, M.; Nupponen, N.N.; Abdel-Rahman, W.M.; Butzow, R.; Peltomäki, P. Patterns of PIK3CA alterations in familial colorectal and endometrial carcinoma. Int. J. Cancer, 2007, 121(4), 915-920.
[http://dx.doi.org/10.1002/ijc.22768] [PMID: 17471559]
[200]
Gupta, S.; Ramjaun, A.R.; Haiko, P.; Wang, Y.; Warne, P.H.; Nicke, B.; Nye, E.; Stamp, G.; Alitalo, K.; Downward, J. Binding of ras to phosphoinositide 3-kinase p110α is required for ras-driven tumorigenesis in mice. Cell, 2007, 129(5), 957-968.
[http://dx.doi.org/10.1016/j.cell.2007.03.051] [PMID: 17540175]
[201]
Halilovic, E.; She, Q-B.; Ye, Q.; Pagliarini, R.; Sellers, W.R.; Solit, D.B.; Rosen, N. PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling. Cancer Res., 2010, 70(17), 6804-6814.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-0409] [PMID: 20699365]
[202]
Hoeflich, K.P.; O’Brien, C.; Boyd, Z.; Cavet, G.; Guerrero, S.; Jung, K.; Januario, T.; Savage, H.; Punnoose, E.; Truong, T.; Zhou, W.; Berry, L.; Murray, L.; Amler, L.; Belvin, M.; Friedman, L.S.; Lackner, M.R. In vivo antitumor activity of mek and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin. Cancer Res., 2009, 15, 4649-4664.
[203]
Temraz, S.; Mukherji, D.; Shamseddine, A. Dual inhibition of mek and pi3k pathway in kras and braf mutated colorectal cancers. Int. J. Mol. Sci., 2015, 16(9), 22976-22988.
[http://dx.doi.org/10.3390/ijms160922976] [PMID: 26404261]
[204]
Sos, M.L.; Fischer, S.; Ullrich, R.; Peifer, M.; Heuckmann, J.M.; Koker, M.; Heynck, S.; Stückrath, I.; Weiss, J.; Fischer, F.; Michel, K.; Goel, A.; Regales, L.; Politi, K.A.; Perera, S.; Getlik, M.; Heukamp, L.C.; Ansén, S.; Zander, T.; Beroukhim, R.; Kashkar, H.; Shokat, K.M.; Sellers, W.R.; Rauh, D.; Orr, C.; Hoeflich, K.P.; Friedman, L.; Wong, K-K.; Pao, W.; Thomas, R.K. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc. Natl. Acad. Sci. USA, 2009, 106(43), 18351-18356.
[http://dx.doi.org/10.1073/pnas.0907325106] [PMID: 19805051]
[205]
Wee, S.; Jagani, Z.; Xiang, K.X.; Loo, A.; Dorsch, M.; Yao, Y-M.; Sellers, W.R.; Lengauer, C.; Stegmeier, F. PI3K pathway activation mediates resistance to mek inhibitors in kras mutant cancers. Cancer Res., 2009, 69, 4286-4293.
[206]
Ostrem, J.M.; Peters, U.; Sos, M.L.; Wells, J.A.; Shokat, K.M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 2013, 503(7477), 548-551.
[http://dx.doi.org/10.1038/nature12796] [PMID: 24256730]
[207]
Seton-Rogers, S. KRAS-G12C in the crosshairs. Nat. Rev. Cancer, 2020, 20(1), 3.
[http://dx.doi.org/10.1038/s41568-019-0228-3] [PMID: 31728026]
[208]
Ostrem, J.M.L.; Shokat, K.M. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat. Rev. Drug Discov., 2016, 15(11), 771-785.
[http://dx.doi.org/10.1038/nrd.2016.139] [PMID: 27469033]
[209]
Lim, S.M.; Westover, K.D.; Ficarro, S.B.; Harrison, R.A.; Choi, H.G.; Pacold, M.E.; Carrasco, M.; Hunter, J.; Kim, N.D.; Xie, T.; Sim, T.; Jänne, P.A.; Meyerson, M.; Marto, J.A.; Engen, J.R.; Gray, N.S. Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor. Angew. Chem. Int. Ed. Engl., 2014, 53(1), 199-204.
[http://dx.doi.org/10.1002/anie.201307387] [PMID: 24259466]
[210]
Müller, S.; Chaikuad, A.; Gray, N.S.; Knapp, S. The ins and outs of selective kinase inhibitor development. Nat. Chem. Biol., 2015, 11(11), 818-821.
[http://dx.doi.org/10.1038/nchembio.1938] [PMID: 26485069]
[211]
Hunter, J.C.; Gurbani, D.; Ficarro, S.B.; Carrasco, M.A.; Lim, S.M.; Choi, H.G.; Xie, T.; Marto, J.A.; Chen, Z.; Gray, N.S.; Westover, K.D. In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C. Proc. Natl. Acad. Sci. USA, 2014, 111(24), 8895-8900.
[http://dx.doi.org/10.1073/pnas.1404639111] [PMID: 24889603]
[212]
Müller, M.P.; Jeganathan, S.; Heidrich, A.; Campos, J.; Goody, R.S. Nucleotide based covalent inhibitors of KRas can only be efficient in vivo if they bind reversibly with GTP-like affinity. Sci. Rep., 2017, 7(1), 3687.
[http://dx.doi.org/10.1038/s41598-017-03973-6] [PMID: 28623374]
[213]
Westover, K.D.; Jänne, P.A.; Gray, N.S. Progress on covalent inhibition of kras(g12c). Cancer Discov., 2016, 6(3), 233-234.
[http://dx.doi.org/10.1158/2159-8290.CD-16-0092] [PMID: 26951837]
[214]
Canon, J.; Rex, K.; Saiki, A.Y.; Mohr, C.; Cooke, K.; Bagal, D.; Gaida, K.; Holt, T.; Knutson, C.G.; Koppada, N.; Lanman, B.A.; Werner, J.; Rapaport, A.S.; San Miguel, T.; Ortiz, R.; Osgood, T.; Sun, J-R.; Zhu, X.; McCarter, J.D.; Volak, L.P.; Houk, B.E.; Fakih, M.G.; O’Neil, B.H.; Price, T.J.; Falchook, G.S.; Desai, J.; Kuo, J.; Govindan, R.; Hong, D.S.; Ouyang, W.; Henary, H.; Arvedson, T.; Cee, V.J.; Lipford, J.R. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature, 2019, 575(7781), 217-223.
[http://dx.doi.org/10.1038/s41586-019-1694-1] [PMID: 31666701]
[215]
Hallin, J.; Engstrom, L.D.; Hargis, L.; Calinisan, A.; Aranda, R.; Briere, D.M.; Sudhakar, N.; Bowcut, V.; Baer, B.R.; Ballard, J.A.; Burkard, M.R.; Fell, J.B.; Fischer, J.P.; Vigers, G.P.; Xue, Y.; Gatto, S.; Fernandez-Banet, J.; Pavlicek, A.; Velastagui, K.; Chao, R.C.; Barton, J.; Pierobon, M.; Baldelli, E.; Patricoin, E.F., III; Cassidy, D.P.; Marx, M.A.; Rybkin, I.I.; Johnson, M.L.; Ou, S.I.; Lito, P.; Papadopoulos, K.P.; Jänne, P.A.; Olson, P.; Christensen, J.G. The KRASG12C inhibitor mrtx849 provides insight toward therapeutic susceptibility of kras-mutant cancers in mouse models and patients. Cancer Discov., 2020, 10(1), 54-71.
[http://dx.doi.org/10.1158/2159-8290.CD-19-1167] [PMID: 31658955]
[216]
Sheridan, C. Grail of RAS cancer drugs within reach. Nat. Biotechnol., 2020, 38(1), 6-8.
[http://dx.doi.org/10.1038/s41587-019-0382-x] [PMID: 31919443]
[217]
Race for undruggable kras speeds up. Nat. Biotechnol., 2019, 37, 1247.
[218]
Nagasaka, M.; Li, Y.; Sukari, A.; Ou, S.I.; Al-Hallak, M.N.; Azmi, A.S. KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat. Rev., 2020, 84101974
[http://dx.doi.org/10.1016/j.ctrv.2020.101974] [PMID: 32014824]

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