KRAS: A Promising Therapeutic Target for Cancer Treatment

Author(s): Hai-Zhou Wu, Jia-Qi Xiao, Song-Shu Xiao*, Yan Cheng*

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 23 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the most commonly mutated oncogene in human cancer. The developments of many cancers depend on sustained expression and signaling of KRAS, which makes KRAS a high-priority therapeutic target. Scientists have not successfully developed drugs that target KRAS, although efforts have been made last three decades. In this review, we highlight the emerging experimental strategies of impairing KRAS membrane localization and the direct targeting of KRAS. We also conclude the combinatorial therapies and RNA interference technology for the treatment of KRAS mutant cancers. Moreover, the virtual screening approach to discover novel KRAS inhibitors and synthetic lethality interactors of KRAS are discussed in detail.

Keywords: KRAS, Cancer treatment, Mutant cancers, Oncogene, Therapeutic target, Viral oncogene.

Hjortland, G.O.; Meza-Zepeda, L.A.; Beiske, K.; Ree, A.H.; Tveito, S.; Hoifodt, H.; Bohler, P.J.; Hole, K.H.; Myklebost, O.; Fodstad, O.; Smeland, S.; Hovig, E. Genome wide single cell analysis of chemotherapy resistant metastatic cells in a case of gastroesophageal adenocarcinoma. BMC Cancer, 2011, 11, 455.
[] [PMID: 22014070]
Zhou, B.; Der, C.J.; Cox, A.D. The role of wild type RAS isoforms in cancer. Semin. Cell Dev. Biol., 2016, 58, 60-69.
[] [PMID: 27422332]
Pylayeva-Gupta, Y.; Grabocka, E.; Bar-Sagi, D. RAS oncogenes: weaving a tumorigenic web. Nat. Rev. Cancer, 2011, 11(11), 761-774.
[] [PMID: 21993244]
Kim, W.; Lee, S.; Kim, H.S.; Song, M.; Cha, Y.H.; Kim, Y.H.; Shin, J.; Lee, E.S.; Joo, Y.; Song, J.J.; Choi, E.J.; Choi, J.W.; Lee, J.; Kang, M.; Yook, J.I.; Lee, M.G.; Kim, Y.S.; Paik, S.; Kim, H.H. Targeting mutant KRAS with CRISPR-Cas9 controls tumor growth. Genome Res., 2018. [Epub ahead of Print
[] [PMID: 29326299]
Boutin, A.T.; Liao, W.T.; Wang, M.; Hwang, S.S.; Karpinets, T.V.; Cheung, H.; Chu, G.C.; Jiang, S.; Hu, J.; Chang, K.; Vilar, E.; Song, X.; Zhang, J.; Kopetz, S.; Futreal, A.; Wang, Y.A.; Kwong, L.N.; DePinho, R.A. Oncogenic Kras drives invasion and maintains metastases in colorectal cancer. Genes Dev., 2017, 31(4), 370-382.
[] [PMID: 28289141]
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
[] [PMID: 25633745]
Yang, S.; Yu, X.; Fan, Y.; Shi, X.; Jin, Y. Clinicopathologic characteristics and survival outcome in patients with advanced lung adenocarcinoma and KRAS mutation. J. Cancer, 2018, 9(16), 2930-2937.
[] [PMID: 30123361]
Li, W.; Qiu, T.; Zhi, W.; Shi, S.; Zou, S.; Ling, Y.; Shan, L.; Ying, J.; Lu, N. Colorectal carcinomas with KRAS codon 12 mutation are associated with more advanced tumor stages. BMC Cancer, 2015, 15, 340.
[] [PMID: 25929517]
Yoon, H.H.; Tougeron, D.; Shi, Q.; Alberts, S.R.; Mahoney, M.R.; Nelson, G.D.; Nair, S.G.; Thibodeau, S.N.; Goldberg, R.M.; Sargent, D.J.; Sinicrope, F.A. KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance). Clin. Cancer Res., 2014, 20(11), 3033-3043.
[] [PMID: 24687927]
Fiala, O.; Buchler, T.; Mohelnikova-Duchonova, B.; Melichar, B.; Matejka, V.M.; Holubec, L.; Kulhankova, J.; Bortlicek, Z.; Bartouskova, M.; Liska, V.; Topolcan, O.; Sedivcova, M.; Finek, J. G12V and G12A KRAS mutations are associated with poor outcome in patients with metastatic colorectal cancer treated with bevacizumab. Tumour Biol., 2016, 37(5), 6823-6830.
[] [PMID: 26662311]
Margonis, G.A.; Kim, Y.; Spolverato, G.; Ejaz, A.; Gupta, R.; Cosgrove, D.; Anders, R.; Karagkounis, G.; Choti, M.A.; Pawlik, T.M. Association between specific mutations in KRAS codon 12 and colorectal liver metastasis. JAMA Surg., 2015, 150(8), 722-729.
[] [PMID: 26038887]
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.
[] [PMID: 28208157]
Cox, A.D.; Fesik, S.W.; Kimmelman, A.C.; Luo, J.; Der, C.J. Drugging the undruggable RAS: Mission possible? Nat. Rev. Drug Discov., 2014, 13(11), 828-851.
[] [PMID: 25323927]
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.
[] [PMID: 29455666]
Muzumdar, M.D.; Chen, P.Y.; Dorans, K.J.; Chung, K.M.; Bhutkar, A.; Hong, E.; Noll, E.M.; Sprick, M.R.; Trumpp, A.; Jacks, T. Survival of pancreatic cancer cells lacking KRAS function. Nat. Commun., 2017, 8(1), 1090.
[] [PMID: 29061961]
Thompson, K.N.; Whipple, R.A.; Yoon, J.R.; Lipsky, M.; Charpentier, M.S.; Boggs, A.E.; Chakrabarti, K.R.; Bhandary, L.; Hessler, L.K.; Martin, S.S.; Vitolo, M.I. The combinatorial activation of the PI3K and Ras/MAPK pathways is sufficient for aggressive tumor formation, while individual pathway activation supports cell persistence. Oncotarget, 2015, 6(34), 35231-35246.
[] [PMID: 26497685]
Dai, X.; Xia, H.; Zhou, S.; Tang, Q.; Bi, F. Zoledronic acid enhances the efficacy of the MEK inhibitor trametinib in KRAS mutant cancers. Cancer Lett., 2019, 442, 202-212.
[] [PMID: 30429107]
Hong, D.S.; Cabanillas, M.E.; Wheler, J.; Naing, A.; Tsimberidou, A.M.; Ye, L.; Busaidy, N.L.; Waguespack, S.G.; Hernandez, M.; El Naggar, A.K.; Bidyasar, S.; Wright, J.; Sherman, S.I.; Kurzrock, R. Inhibition of the Ras/Raf/MEK/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies. J. Clin. Endocrinol. Metab., 2011, 96(4), 997-1005.
[] [PMID: 21289252]
Balasis, M.E.; Forinash, K.D.; Chen, Y.A.; Fulp, W.J.; Coppola, D.; Hamilton, A.D.; Cheng, J.Q.; Sebti, S.M. Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant breast tumor regression in ErbB2 transgenic mice. Clin. Cancer Res., 2011, 17(9), 2852-2862.
[] [PMID: 21536547]
Bergo, M.O.; Ambroziak, P.; Gregory, C.; George, A.; Otto, J.C.; Kim, E.; Nagase, H.; Casey, P.J.; Balmain, A.; Young, S.G. Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. Mol. Cell. Biol., 2002, 22(1), 171-181.
[] [PMID: 11739732]
Mohammed, I.; Hampton, S.E.; Ashall, L.; Hildebrandt, E.R.; Kutlik, R.A.; Manandhar, S.P.; Floyd, B.J.; Smith, H.E.; Dozier, J.K.; Distefano, M.D.; Schmidt, W.K.; Dore, T.M. 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells. Bioorg. Med. Chem., 2016, 24(2), 160-178.
[] [PMID: 26706114]
Lau, H.Y.; Tang, J.; Casey, P.J.; Wang, M. Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms. Oncogene, 2017, 36(27), 3934-3942.
[] [PMID: 28192404]
Lau, H.Y.; Ramanujulu, P.M.; Guo, D.; Yang, T.; Wirawan, M.; Casey, P.J.; Go, M.L.; Wang, M. An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo. Cancer Biol. Ther., 2014, 15(9), 1280-1291.
[] [PMID: 24971579]
Gbelcová, H.; Rimpelová, S.; Knejzlík, Z.; Šáchová, J.; Kolář, M.; Strnad, H.; Repiská, V.; D’Acunto, W.C.; Ruml, T.; Vítek, L. Isoprenoids responsible for protein prenylation modulate the biological effects of statins on pancreatic cancer cells. Lipids Health Dis., 2017, 16(1), 250.
[] [PMID: 29262834]
Zhao, H.; Liu, P.; Zhang, R.; Wu, M.; Li, D.; Zhao, X.; Zhang, C.; Jiao, B.; Chen, B.; Chen, Z.; Ren, R. Roles of palmitoylation and the KIKK membrane-targeting motif in leukemogenesis by oncogenic KRAS4A. J. Hematol. Oncol., 2015, 8, 132.
[] [PMID: 26715448]
Barceló, C.; Paco, N.; Morell, M.; Alvarez-Moya, B.; Bota-Rabassedas, N.; Jaumot, M.; Vilardell, F.; Capella, G.; Agell, N. Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth. Cancer Res., 2014, 74(4), 1190-1199.
[] [PMID: 24371225]
Agamasu, C.; Ghirlando, R.; Taylor, T.; Messing, S.; Tran, T.H.; Bindu, L.; Tonelli, M.; Nissley, D.V.; McCormick, F.; Stephen, A.G. KRAS prenylation is required for bivalent binding with calmodulin in a nucleotide-independent manner. Biophys. J., 2019, 116(6), 1049-1063.
[] [PMID: 30846362]
Sperlich, B.; Kapoor, S.; Waldmann, H.; Winter, R.; Weise, K. Regulation of K-Ras4B membrane binding by calmodulin. Biophys. J., 2016, 111(1), 113-122.
[] [PMID: 27410739]
van der Hoeven, D.; Cho, K.J.; Ma, X.; Chigurupati, S.; Parton, R.G.; Hancock, J.F. Fendiline inhibits K-Ras plasma membrane localization and blocks K-Ras signal transmission. Mol. Cell. Biol., 2013, 33(2), 237-251.
[] [PMID: 23129805]
Jang, H.; Banerjee, A.; Chavan, T.; Gaponenko, V.; Nussinov, R. Flexible-body motions of calmodulin and the farnesylated hypervariable region yield a high-affinity interaction enabling K-Ras4B membrane extraction. J. Biol. Chem., 2017, 292(30), 12544-12559.
[] [PMID: 28623230]
Najumudeen, A.K.; Jaiswal, A.; Lectez, B.; Oetken-Lindholm, C.; Guzmán, C.; Siljamäki, E.; Posada, I.M.; Lacey, E.; Aittokallio, T.; Abankwa, D. Cancer stem cell drugs target K-ras signaling in a stemness context. Oncogene, 2016, 35(40), 5248-5262.
[] [PMID: 26973241]
Dharmaiah, S.; Bindu, L.; Tran, T.H.; Gillette, W.K.; Frank, P.H.; Ghirlando, R.; Nissley, D.V.; Esposito, D.; McCormick, F.; Stephen, A.G.; Simanshu, D.K. Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ. Proc. Natl. Acad. Sci. USA, 2016, 113(44), E6766-E6775.
[] [PMID: 27791178]
Papke, B.; Murarka, S.; Vogel, H.A.; Martín-Gago, P.; Kovacevic, M.; Truxius, D.C.; Fansa, E.K.; Ismail, S.; Zimmermann, G.; Heinelt, K.; Schultz-Fademrecht, C.; Al Saabi, A.; Baumann, M.; Nussbaumer, P.; Wittinghofer, A.; Waldmann, H.; Bastiaens, P.I. Identification of pyrazolopyridazinones as PDEδ inhibitors. Nat. Commun., 2016, 7, 11360.
[] [PMID: 27094677]
Leung, E.L.H.; Luo, L.X.; Liu, Z.Q.; Wong, V.K.W.; Lu, L.L.; Xie, Y.; Zhang, N.; Qu, Y.Q.; Fan, X.X.; Li, Y.; Huang, M.; Xiao, D.K.; Huang, J.; Zhou, Y.L.; He, J.X.; Ding, J.; Yao, X.J.; Ward, D.C.; Liu, L. Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity. Cell Death Dis., 2018, 9(2), 216.
[] [PMID: 29440631]
Leung, E.L.; Luo, L.X.; Li, Y.; Liu, Z.Q.; Li, L.L.; Shi, D.F.; Xie, Y.; Huang, M.; Lu, L.L.; Duan, F.G.; Huang, J.M.; Fan, X.X.; Yuan, Z.W.; Ding, J.; Yao, X.J.; Ward, D.C.; Liu, L. Identification of a new inhibitor of KRAS-PDEδ interaction targeting KRAS mutant nonsmall cell lung cancer. Int. J. Cancer, 2019, 145(5), 1334-1345.
[] [PMID: 30786019]
Fehrenbacher, N.; Tojal da Silva, I.; Ramirez, C.; Zhou, Y.; Cho, K.J.; Kuchay, S.; Shi, J.; Thomas, S.; Pagano, M.; Hancock, J.F.; Bar-Sagi, D.; Philips, M.R. The G protein-coupled receptor GPR31 promotes membrane association of KRAS. J. Cell Biol., 2017, 216(8), 2329-2338.
[] [PMID: 28619714]
Gulyás, G.; Radvánszki, G.; Matuska, R.; Balla, A.; Hunyady, L.; Balla, T.; Várnai, P. Plasma membrane phosphatidylinositol 4-phosphate and 4,5-bisphosphate determine the distribution and function of K-Ras4B but not H-Ras proteins. J. Biol. Chem., 2017, 292(46), 18862-18877.
[] [PMID: 28939768]
Mustachio, L.M.; Lu, Y.; Tafe, L.J.; Memoli, V.; Rodriguez-Canales, J.; Mino, B.; Villalobos, P.A.; Wistuba, I.; Katayama, H.; Hanash, S.M.; Roszik, J.; Kawakami, M.; Cho, K.J.; Hancock, J.F.; Chinyengetere, F.; Hu, S.; Liu, X.; Freemantle, S.J.; Dmitrovsky, E. Deubiquitinase USP18 loss mislocalizes and destabilizes KRAS in lung cancer. Mol. Cancer Res., 2017, 15(7), 905-914.
[] [PMID: 28242811]
Nadal, E.; Chen, G.; Prensner, J.R.; Shiratsuchi, H.; Sam, C.; Zhao, L.; Kalemkerian, G.P.; Brenner, D.; Lin, J.; Reddy, R.M.; Chang, A.C.; Capellà, G.; Cardenal, F.; Beer, D.G.; Ramnath, N. KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma. J. Thorac. Oncol., 2014, 9(10), 1513-1522.
[] [PMID: 25170638]
Monticone, M.; Biollo, E.; Maffei, M.; Donadini, A.; Romeo, F.; Storlazzi, C.T.; Giaretti, W.; Castagnola, P. Gene expression deregulation by KRAS G12D and G12V in a BRAF V600E context. Mol. Cancer, 2008, 7, 92.
[] [PMID: 19087308]
Lito, P.; Solomon, M.; Li, L.S.; Hansen, R.; Rosen, N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science, 2016, 351(6273), 604-608.
[] [PMID: 26841430]
Janes, M.R.; Zhang, J.; Li, L.S.; Hansen, R.; Peters, U.; Guo, X.; Chen, Y.; Babbar, A.; Firdaus, S.J.; Darjania, L.; Feng, J.; Chen, J.H.; Li, S.; Li, S.; Long, Y.O.; Thach, C.; Liu, Y.; Zarieh, A.; Ely, T.; Kucharski, J.M.; Kessler, L.V.; Wu, T.; Yu, K.; Wang, Y.; Yao, Y.; Deng, X.; Zarrinkar, P.P.; Brehmer, D.; Dhanak, D.; Lorenzi, M.V.; Hu-Lowe, D.; Patricelli, M.P.; Ren, P.; Liu, Y. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell, 2018, 172, 578-589.
[] [PMID: 29373830]
Carver, J.; Dexheimer, T.S.; Hsu, D.; Weng, M.T.; Smith, J.L.; Guha, R.; Jadhav, A.; Simeonov, A.; Luo, J. A high-throughput assay for small molecule destabilizers of the KRAS oncoprotein. PLoS One, 2014, 9(8), e103836.
[] [PMID: 25093678]
Jang, H.; Muratcioglu, S.; Gursoy, A.; Keskin, O.; Nussinov, R. Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers. Biochem. J., 2016, 473(12), 1719-1732.
[] [PMID: 27057007]
Nan, X.; Tamgüney, T.M.; Collisson, E.A.; Lin, L.J.; Pitt, C.; Galeas, J.; Lewis, S.; Gray, J.W.; McCormick, F.; Chu, S. Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway. Proc. Natl. Acad. Sci. USA, 2015, 112(26), 7996-8001.
[] [PMID: 26080442]
Muratcioglu, S.; Chavan, T.S.; Freed, B.C.; Jang, H.; Khavrutskii, L.; Freed, R.N.; Dyba, M.A.; Stefanisko, K.; Tarasov, S.G.; Gursoy, A.; Keskin, O.; Tarasova, N.I.; Gaponenko, V.; Nussinov, R. GTP-Dependent K-Ras Dimerization. Structure, 2015, 23(7), 1325-1335.
[] [PMID: 26051715]
Ambrogio, C.; Kohler, J.; Zhou, Z.W.; Wang, H.; Paranal, R.; Li, J.; Capelletti, M.; Caffarra, C.; Li, S.; Lv, Q.; Gondi, S.; Hunter, J.C.; Lu, J.; Chiarle, R.; Santamaria, D.; Westover, K.D.; Janne, P.A. KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS. Cell, 2018, 172, 857-868.
[] [PMID: 29336889]
Tornaletti, S.; Park-Snyder, S.; Hanawalt, P.C. G4-forming sequences in the non-transcribed DNA strand pose blocks to T7 RNA polymerase and mammalian RNA polymerase II. J. Biol. Chem., 2008, 283(19), 12756-12762.
[] [PMID: 18292094]
Hegyi, H. Enhancer-promoter interaction facilitated by transiently forming G-quadruplexes. Sci. Rep., 2015, 5, 9165.
[] [PMID: 25772493]
Cogoi, S.; Xodo, L.E. G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription. Nucleic Acids Res., 2006, 34(9), 2536-2549.
[] [PMID: 16687659]
Li, Y.; Zhang, X.; Gao, Y.; Shi, J.; Tang, L.; Sui, G. G-quadruplexes in the BAP1 promoter positively regulate its expression. Exp. Cell Res., 2018, 369(1), 147-157.
[] [PMID: 29787736]
Morgan, R.K.; Batra, H.; Gaerig, V.C.; Hockings, J.; Brooks, T.A. Identification and characterization of a new G-quadruplex forming region within the kRAS promoter as a transcriptional regulator. Biochim. Biophys. Acta, 2016, 1859(2), 235-245.
[] [PMID: 26597160]
Francisco, A.P.; Paulo, A. Oncogene expression modulation in cancer cell lines by DNA G-quadruplex-interactive small molecules. Curr. Med. Chem., 2017, 24(42), 4873-4904.
[PMID: 27573064]
Brito, H.; Martins, A.C.; Lavrado, J.; Mendes, E.; Francisco, A.P.; Santos, S.A.; Ohnmacht, S.A.; Kim, N.S.; Rodrigues, C.M.; Moreira, R.; Neidle, S.; Borralho, P.M.; Paulo, A. Targeting KRAS oncogene in colon cancer cells with 7-carboxylate indolo[3,2-b]quinoline tri-alkylamine derivatives. PLoS One, 2015, 10(5)e0126891
[] [PMID: 26024321]
Lavrado, J.; Brito, H.; Borralho, P.M.; Ohnmacht, S.A.; Kim, N.S.; Leitão, C.; Pisco, S.; Gunaratnam, M.; Rodrigues, C.M.; Moreira, R.; Neidle, S.; Paulo, A. KRAS oncogene repression in colon cancer cell lines by G-quadruplex binding indolo[3,2-c]quinolines. Sci. Rep., 2015, 5, 9696.
[] [PMID: 25853628]
Jana, J.; Mondal, S.; Bhattacharjee, P.; Sengupta, P.; Roychowdhury, T.; Saha, P.; Kundu, P.; Chatterjee, S. Chelerythrine down regulates expression of VEGFA, BCL2 and KRAS by arresting G-Quadruplex structures at their promoter regions. Sci. Rep., 2017, 7, 40706.
[] [PMID: 28102286]
Carvalho, J.; Pereira, E.; Marquevielle, J.; Campello, M.P.C.; Mergny, J.L.; Paulo, A.; Salgado, G.F.; Queiroz, J.A.; Cruz, C. Fluorescent light-up acridine orange derivatives bind and stabilize KRAS-22RT G-quadruplex. Biochimie, 2018, 144, 144-152.
[] [PMID: 29129745]
Pattanayak, R.; Barua, A.; Das, A.; Chatterjee, T.; Pathak, A.; Choudhury, P.; Sen, S.; Saha, P.; Bhattacharyya, M. Porphyrins to restrict progression of pancreatic cancer by stabilizing KRAS G-quadruplex: In silico, in vitro and in vivo validation of anticancer strategy. Eur. J. Pharm. Sci., 2018, 125, 39-53.
[] [PMID: 30223034]
Calabrese, D.R.; Zlotkowski, K.; Alden, S.; Hewitt, W.M.; Connelly, C.M.; Wilson, R.M.; Gaikwad, S.; Chen, L.; Guha, R.; Thomas, C.J.; Mock, B.A.; Schneekloth, J.S., Jr Characterization of clinically used oral antiseptics as quadruplex-binding ligands. Nucleic Acids Res., 2018, 46(6), 2722-2732.
[] [PMID: 29481610]
Sogabe, S.; Kamada, Y.; Miwa, M.; Niida, A.; Sameshima, T.; Kamaura, M.; Yonemori, K.; Sasaki, S.; Sakamoto, J.I.; Sakamoto, K. Crystal structure of a human K-Ras G12D mutant in complex with GDP and the cyclic inhibitory peptide KRpep-2d. ACS Med. Chem. Lett., 2017, 8(7), 732-736.
[] [PMID: 28740607]
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.
[] [PMID: 24889603]
Pathan, A.A.; Panthi, B.; Khan, Z.; Koppula, P.R.; Alanazi, M.S. Sachchidanand; Parine, N.R.; Chourasia, M. Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches. OncoTargets Ther., 2016, 9, 2575-2584.
[] [PMID: 27217775]
Xie, C.; Li, Y.; Li, L.L.; Fan, X.X.; Wang, Y.W.; Wei, C.L.; Liu, L.; Leung, E.L.; Yao, X.J. Identification of a new potent inhibitor targeting kras in non-small cell lung cancer cells. Front. Pharmacol., 2017, 8, 823.
[] [PMID: 29184501]
Nnadi, C.I.; Jenkins, M.L.; Gentile, D.R.; Bateman, L.A.; Zaidman, D.; Balius, T.E.; Nomura, D.K.; Burke, J.E.; Shokat, K.M.; London, N. Novel K-Ras G12C Switch-II covalent binders destabilize Ras and accelerate nucleotide exchange. J. Chem. Inf. Model., 2018, 58(2), 464-471.
[] [PMID: 29320178]
Zeng, M.; Lu, J.; Li, L.; Feru, F.; Quan, C.; Gero, T.W.; Ficarro, S.B.; Xiong, Y.; Ambrogio, C.; Paranal, R.M.; Catalano, M.; Shao, J.; Wong, K.K.; Marto, J.A.; Fischer, E.S.; Janne, P.A.; Scott, D.A.; Westover, K.D.; Gray, N.S. Potent and selective covalent quinazoline inhibitors of KRAS G12C. Cell Chem. Biol., 2017, 24, 1005-1016.
[] [PMID: 28781124]
Fell, J.B.; Fischer, J.P.; Baer, B.R.; Ballard, J.; Blake, J.F.; Bouhana, K.; Brandhuber, B.J.; Briere, D.M.; Burgess, L.E.; Burkard, M.R.; Chiang, H.; Chicarelli, M.J.; Davidson, K.; Gaudino, J.J.; Hallin, J.; Hanson, L.; Hee, K.; Hicken, E.J.; Hinklin, R.J.; Marx, M.A.; Mejia, M.J.; Olson, P.; Savechenkov, P.; Sudhakar, N.; Tang, T.P.; Vigers, G.P.; Zecca, H.; Christensen, J.G. Discovery of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. ACS Med. Chem. Lett., 2018, 9(12), 1230-1234.
[] [PMID: 30613331]
Hocker, H.J.; Cho, K.J.; Chen, C.Y.; Rambahal, N.; Sagineedu, S.R.; Shaari, K.; Stanslas, J.; Hancock, J.F.; Gorfe, A.A. Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function. Proc. Natl. Acad. Sci. USA, 2013, 110(25), 10201-10206.
[] [PMID: 23737504]
You, X.; Kong, G.; Ranheim, E.A.; Yang, D.; Zhou, Y.; Zhang, J. Unique dependence on Sos1 in KrasG12D -induced leukemogenesis. Blood, 2018, 132(24), 2575-2579.
[] [PMID: 30377195]
Fatima, A.; Yee, H.F. In Silico screening of mutated K-Ras inhibitors from malaysian typhonium flagelliforme for non-small cell lung cancer. Adv. Bioinformatics., 2014, 2014, 43169.
[] [PMID: 25309590]
Hillig, R.C.; Sautier, B.; Schroeder, J.; Moosmayer, D.; Hilpmann, A.; Stegmann, C.M.; Werbeck, N.D.; Briem, H.; Boemer, U.; Weiske, J.; Badock, V.; Mastouri, J.; Petersen, K.; Siemeister, G.; Kahmann, J.D.; Wegener, D.; Böhnke, N.; Eis, K.; Graham, K.; Wortmann, L.; von Nussbaum, F.; Bader, B. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc. Natl. Acad. Sci. USA, 2019, 116(7), 2551-2560.
[] [PMID: 30683722]
Leshchiner, E.S.; Parkhitko, A.; Bird, G.H.; Luccarelli, J.; Bellairs, J.A.; Escudero, S.; Opoku-Nsiah, K.; Godes, M.; Perrimon, N.; Walensky, L.D. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. Proc. Natl. Acad. Sci. USA, 2015, 112(6), 1761-1766.
[] [PMID: 25624485]
Huang, L.; Carney, J.; Cardona, D.M.; Counter, C.M. Decreased tumorigenesis in mice with a Kras point mutation at C118. Nat. Commun., 2014, 5, 5410.
[] [PMID: 25394415]
Winter, J.J.; Anderson, M.; Blades, K.; Brassington, C.; Breeze, A.L.; Chresta, C.; Embrey, K.; Fairley, G.; Faulder, P.; Finlay, M.R.; Kettle, J.G.; Nowak, T.; Overman, R.; Patel, S.J.; Perkins, P.; Spadola, L.; Tart, J.; Tucker, J.A.; Wrigley, G. Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation. J. Med. Chem., 2015, 58(5), 2265-2274.
[] [PMID: 25695162]
The KRAS-PDEδ interaction is a therapeutic target. Cancer Discov., 2013, 3(7), OF20.
[ 10.1158/2159-8290.CD-RW2013-116] [PMID: 23847364]
Cruz-Nova, P.; Schnoor, M.; Correa-Basurto, J.; Bello, M.; Briseño-Diaz, P.; Rojo-Domínguez, A.; Ortiz-Mendoza, C.M.; Guerrero-Aguirre, J.; García-Vázquez, F.J.; Hernández-Rivas, R.; Thompson-Bonilla, M.D.R.; Vargas, M. The small organic molecule C19 binds and strengthens the KRAS4b-PDEδ complex and inhibits growth of colorectal cancer cells in vitro and in vivo. BMC Cancer, 2018, 18(1), 1056.
[] [PMID: 30382908]
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.
[] [PMID: 30594165]
Apaolaza, I.; San José-Eneriz, E.; Tobalina, L.; Miranda, E.; Garate, L.; Agirre, X.; Prósper, F.; Planes, F.J. An in-silico approach to predict and exploit synthetic lethality in cancer metabolism. Nat. Commun., 2017, 8(1), 459.
[] [PMID: 28878380]
Jones, M.F.; Hara, T.; Lal, A. KRAS Cold Turkey: Using microRNAs to target KRAS-addicted cancer. RNA Dis., 2015, 2(1), e539.
[] [PMID: 29367950]
Shen, H.; Xing, C.; Cui, K.; Li, Y.; Zhang, J.; Du, R.; Zhang, X.; Li, Y. MicroRNA-30a attenuates mutant KRAS-driven colorectal tumorigenesis via direct suppression of ME1. Cell Death Differ., 2017, 24(7), 1253-1262.
[] [PMID: 28475173]
Acunzo, M.; Romano, G.; Nigita, G.; Veneziano, D.; Fattore, L.; Laganà, A.; Zanesi, N.; Fadda, P.; Fassan, M.; Rizzotto, L.; Kladney, R.; Coppola, V.; Croce, C.M. Selective targeting of point-mutated KRAS through artificial microRNAs. Proc. Natl. Acad. Sci. USA, 2017, 114(21), E4203-E4212.
[] [PMID: 28484014]
Ferino, A.; Miglietta, G.; Picco, R.; Vogel, S.; Wengel, J.; Xodo, L.E. MicroRNA therapeutics: design of single-stranded miR-216b mimics to target KRAS in pancreatic cancer cells. RNA Biol., 2018, 15(10), 1273-1285.
[] [PMID: 30306823]
Neu, J.; Dziunycz, P.J.; Dzung, A.; Lefort, K.; Falke, M.; Denzler, R.; Freiberger, S.N.; Iotzova-Weiss, G.; Kuzmanov, A.; Levesque, M.P.; Dotto, G.P.; Hofbauer, G.F.L. miR-181a decelerates proliferation in cutaneous squamous cell carcinoma by targeting the proto-oncogene KRAS. PLoS One, 2017, 12(9)e0185028
[] [PMID: 28931048]
Han, Z.; Yang, Q.; Liu, B.; Wu, J.; Li, Y.; Yang, C.; Jiang, Y. MicroRNA-622 functions as a tumor suppressor by targeting K-Ras and enhancing the anticarcinogenic effect of resveratrol. Carcinogenesis, 2012, 33(1), 131-139.
[] [PMID: 22016468]
Wang, X.F.; Shi, Z.M.; Wang, X.R.; Cao, L.; Wang, Y.Y.; Zhang, J.X.; Yin, Y.; Luo, H.; Kang, C.S.; Liu, N.; Jiang, T.; You, Y.P. MiR-181d acts as a tumor suppressor in glioma by targeting K-ras and Bcl-2. J. Cancer Res. Clin. Oncol., 2012, 138(4), 573-584.
[] [PMID: 22207524]
Liu, Y.; Zhang, M.; Qian, J.; Bao, M.; Meng, X.; Zhang, S.; Zhang, L.; Zhao, R.; Li, S.; Cao, Q.; Li, P.; Ju, X.; Lu, Q.; Li, J.; Shao, P.; Qin, C.; Yin, C. miR-134 functions as a tumor suppressor in cell proliferation and epithelial-to-mesenchymal Transition by targeting KRAS in renal cell carcinoma cells. DNA Cell Biol., 2015, 34(6), 429-436.
[] [PMID: 25811077]
Hiraki, M.; Nishimura, J.; Takahashi, H.; Wu, X.; Takahashi, Y.; Miyo, M.; Nishida, N.; Uemura, M.; Hata, T.; Takemasa, I.; Mizushima, T.; Soh, J.W.; Doki, Y.; Mori, M.; Yamamoto, H. Concurrent targeting of KRAS and AKT by MiR-4689 is a novel treatment against mutant KRAS colorectal cancer. Mol. Ther. Nucleic Acids, 2015, 4e231
[] [PMID: 25756961]
Seviour, E.G.; Sehgal, V.; Mishra, D.; Rupaimoole, R.; Rodriguez-Aguayo, C.; Lopez-Berestein, G.; Lee, J.S.; Sood, A.K.; Kim, M.P.; Mills, G.B.; Ram, P.T. Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p. Oncogene, 2017, 36(10), 1339-1350.
[] [PMID: 27669434]
Gu, L.; Deng, Z.J.; Roy, S.; Hammond, P.T. A Combination RNAi-chemotherapy layer-by-layer nanoparticle for systemic targeting of KRAS/P53 with cisplatin to treat non-small cell lung cancer. Clin. Cancer Res., 2017, 23(23), 7312-7323.
[] [PMID: 28912139]
Zhang, Y.; Zhao, Y.; Liu, L.; Su, H.; Dong, D.; Wang, J.; Zhang, Y.; Chen, Q.; Li, C. MicroRNA-19b promotes nasopharyngeal carcinoma more sensitive to cisplatin by suppressing KRAS. Technol. Cancer Res. Treat., 2018, 171533033818793652
[] [PMID: 30231694]
Yin, Z.; Ren, W. MicroRNA-217 acts as a tumor suppressor and correlates with the chemoresistance of cervical carcinoma to cisplatin. OncoTargets Ther., 2019, 12, 759-771.
[] [PMID: 30774364]
Mao, C.Q.; Xiong, M.H.; Liu, Y.; Shen, S.; Du, X.J.; Yang, X.Z.; Dou, S.; Zhang, P.Z.; Wang, J. Synthetic lethal therapy for KRAS mutant non-small-cell lung carcinoma with nanoparticle-mediated CDK4 siRNA delivery. Mol. Ther., 2014, 22(5), 964-973.
[] [PMID: 24496383]
Costa-Cabral, S.; Brough, R.; Konde, A.; Aarts, M.; Campbell, J.; Marinari, E.; Riffell, J.; Bardelli, A.; Torrance, C.; Lord, C.J.; Ashworth, A. Correction: CDK1 is a synthetic lethal target for KRAS mutant tumours. PLoS One, 2017, 12(4)e0176578
[] [PMID: 28426773]
Wang, J.; Hu, K.; Guo, J.; Cheng, F.; Lv, J.; Jiang, W.; Lu, W.; Liu, J.; Pang, X.; Liu, M. Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK. Nat. Commun., 2016, 7, 11363.
[] [PMID: 27193833]
Sarthy, A.V.; Morgan-Lappe, S.E.; Zakula, D.; Vernetti, L.; Schurdak, M.; Packer, J.C.; Anderson, M.G.; Shirasawa, S.; Sasazuki, T.; Fesik, S.W. Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells. Mol. Cancer Ther., 2007, 6(1), 269-276.
[] [PMID: 17237286]
Licciulli, S.; Kissil, J.L. WT1: a weak spot in KRAS-induced transformation. J. Clin. Invest., 2010, 120(11), 3804-3807.
[] [PMID: 20972324]
Steckel, M.; Molina-Arcas, M.; Weigelt, B.; Marani, M.; Warne, P.H.; Kuznetsov, H.; Kelly, G.; Saunders, B.; Howell, M.; Downward, J.; Hancock, D.C. Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies. Cell Res., 2012, 22(8), 1227-1245.
[] [PMID: 22613949]
Kim, J.; McMillan, E.; Kim, H.S.; Venkateswaran, N.; Makkar, G.; Rodriguez-Canales, J.; Villalobos, P.; Neggers, J.E.; Mendiratta, S.; Wei, S.; Landesman, Y.; Senapedis, W.; Baloglu, E.; Chow, C.B.; Frink, R.E.; Gao, B.; Roth, M.; Minna, J.D.; Daelemans, D.; Wistuba, I.I.; Posner, B.A.; Scaglioni, P.P.; White, M.A. XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature, 2016, 538(7623), 114-117.
[] [PMID: 27680702]
Barbie, D.A.; Tamayo, P.; Boehm, J.S.; Kim, S.Y.; Moody, S.E.; Dunn, I.F.; Schinzel, A.C.; Sandy, P.; Meylan, E.; Scholl, C.; Fröhling, S.; Chan, E.M.; Sos, M.L.; Michel, K.; Mermel, C.; Silver, S.J.; Weir, B.A.; Reiling, J.H.; Sheng, Q.; Gupta, P.B.; Wadlow, R.C.; Le, H.; Hoersch, S.; Wittner, B.S.; Ramaswamy, S.; Livingston, D.M.; Sabatini, D.M.; Meyerson, M.; Thomas, R.K.; Lander, E.S.; Mesirov, J.P.; Root, D.E.; Gilliland, D.G.; Jacks, T.; Hahn, W.C. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature, 2009, 462(7269), 108-112.
[] [PMID: 19847166]
Singh, A.; Sweeney, M.F.; Yu, M.; Burger, A.; Greninger, P.; Benes, C.; Haber, D.A.; Settleman, J. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell, 2012, 148(4), 639-650.
[] [PMID: 22341439]
Ma, Q.; Gu, L.; Liao, S.; Zheng, Y.; Zhang, S.; Cao, Y.; Zhang, J.; Wang, Y. NG25, a novel inhibitor of TAK1, suppresses KRAS-mutant colorectal cancer growth in vitro and in vivo. Apoptosis, 2019, 24(1-2), 83-94.
[] [PMID: 30515612]
Zhou, J.; Zheng, B.; Ji, J.; Shen, F.; Min, H.; Liu, B.; Wu, J.; Zhang, S. LYTAK1, a novel TAK1 inhibitor, suppresses KRAS mutant colorectal cancer cell growth in vitro and in vivo. Tumour Biol., 2015, 36(5), 3301-3308.
[] [PMID: 25524577]
Scholl, C.; Fröhling, S.; Dunn, I.F.; Schinzel, A.C.; Barbie, D.A.; Kim, S.Y.; Silver, S.J.; Tamayo, P.; Wadlow, R.C.; Ramaswamy, S.; Döhner, K.; Bullinger, L.; Sandy, P.; Boehm, J.S.; Root, D.E.; Jacks, T.; Hahn, W.C.; Gilliland, D.G. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell, 2009, 137(5), 821-834.
[] [PMID: 19490892]
Luo, T.; Masson, K.; Jaffe, J.D.; Silkworth, W.; Ross, N.T.; Scherer, C.A.; Scholl, C.; Fröhling, S.; Carr, S.A.; Stern, A.M.; Schreiber, S.L.; Golub, T.R. STK33 kinase inhibitor BRD-8899 has no effect on KRAS-dependent cancer cell viability. Proc. Natl. Acad. Sci. USA, 2012, 109(8), 2860-2865.
[] [PMID: 22323609]
Konstantinidou, G.; Ramadori, G.; Torti, F.; Kangasniemi, K.; Ramirez, R.E.; Cai, Y.; Behrens, C.; Dellinger, M.T.; Brekken, R.A.; Wistuba, I.I.; Heguy, A.; Teruya-Feldstein, J.; Scaglioni, P.P. RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discov., 2013, 3(4), 444-457.
[] [PMID: 23358651]
Shaw, A.T.; Winslow, M.M.; Magendantz, M.; Ouyang, C.; Dowdle, J.; Subramanian, A.; Lewis, T.A.; Maglathin, R.L.; Tolliday, N.; Jacks, T. Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc. Natl. Acad. Sci. USA, 2011, 108(21), 8773-8778.
[] [PMID: 21555567]
Hähnel, P.S.; Enders, B.; Sasca, D.; Roos, W.P.; Kaina, B.; Bullinger, L.; Theobald, M.; Kindler, T. Targeting components of the alternative NHEJ pathway sensitizes KRAS mutant leukemic cells to chemotherapy. Blood, 2014, 123(15), 2355-2366.
[] [PMID: 24505083]
Martin, T.D.; Cook, D.R.; Choi, M.Y.; Li, M.Z.; Haigis, K.M.; Elledge, S.J. A role for mitochondrial translation in promotion of viability in K-Ras mutant cells. Cell Rep., 2017, 20(2), 427-438.
[] [PMID: 28700943]
Weinberg, F.; Hamanaka, R.; Wheaton, W.W.; Weinberg, S.; Joseph, J.; Lopez, M.; Kalyanaraman, B.; Mutlu, G.M.; Budinger, G.R.; Chandel, N.S. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl. Acad. Sci. USA, 2010, 107(19), 8788-8793.
[] [PMID: 20421486]
Liou, G.Y.; Döppler, H.; DelGiorno, K.E.; Zhang, L.; Leitges, M.; Crawford, H.C.; Murphy, M.P.; Storz, P. Mutant KRas-induced mitochondrial oxidative stress in acinar cells upregulates EGFR signaling to drive formation of pancreatic precancerous lesions. Cell Rep., 2016, 14(10), 2325-2336.
[] [PMID: 26947075]
Yau, E.H.; Kummetha, I.R.; Lichinchi, G.; Tang, R.; Zhang, Y.; Rana, T.M. Genome-wide CRISPR screen for essential cell growth mediators in mutant KRAS colorectal cancers. Cancer Res., 2017, 77(22), 6330-6339.
[] [PMID: 28954733]
Koundinya, M.; Sudhalter, J.; Courjaud, A.; Lionne, B.; Touyer, G.; Bonnet, L.; Menguy, I.; Schreiber, I.; Perrault, C.; Vougier, S.; Benhamou, B.; Zhang, B.; He, T.; Gao, Q.; Gee, P.; Simard, D.; Castaldi, M.P.; Tomlinson, R.; Reiling, S.; Barrague, M.; Newcombe, R.; Cao, H.; Wang, Y.; Sun, F.; Murtie, J.; Munson, M.; Yang, E.; Harper, D.; Bouaboula, M.; Pollard, J.; Grepin, C.; Garcia-Echeverria, C.; Cheng, H.; Adrian, F.; Winter, C.; Licht, S.; Cornella-Taracido, I.; Arrebola, R.; Morris, A. Dependence on the pyrimidine biosynthetic enzyme DHODH is a synthetic lethal vulnerability in mutant KRAS-driven cancers. Cell Chem. Biol., 2018, 25, 705-717.
[] [PMID: 29628435]
Saqcena, M.; Mukhopadhyay, S.; Hosny, C.; Alhamed, A.; Chatterjee, A.; Foster, D.A. Blocking anaplerotic entry of glutamine into the TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs. Oncogene, 2015, 34(20), 2672-2680.
[] [PMID: 25023699]
Wong, C.C.; Qian, Y.; Li, X.; Xu, J.; Kang, W.; Tong, J.H.; To, K.F.; Jin, Y.; Li, W.; Chen, H.; Go, M.Y.; Wu, J.L.; Cheng, K.W.; Ng, S.S.; Sung, J.J.; Cai, Z.; Yu, J. SLC25A22 Promotes proliferation and survival of colorectal cancer cells with KRAS mutations and xenograft tumor progression in mice via intracellular synthesis of aspartate. Gastroenterology, 2016, 151, 945-960.
[] [PMID: 27451147 ]
Chakrabarti, G. Mutant KRAS associated malic enzyme 1 expression is a predictive marker for radiation therapy response in non-small cell lung cancer. Radiat. Oncol., 2015, 10, 145.
[] [PMID: 26173780]
Christodoulou, E.G.; Yang, H.; Lademann, F.; Pilarsky, C.; Beyer, A.; Schroeder, M. Detection of COPB2 as a KRAS synthetic lethal partner through integration of functional genomics screens. Oncotarget, 2017, 8(21), 34283-34297.
[] [PMID: 28415695]
Fraile, J.M.; Manchado, E.; Lujambio, A.; Quesada, V.; Campos-Iglesias, D.; Webb, T.R.; Lowe, S.W.; López-Otín, C.; Freije, J.M.P. USP39 deubiquitinase is essential for KRAS oncogene-driven Cancer. J. Biol. Chem., 2017, 292(10), 4164-4175.
[] [PMID: 28154181]
Misale, S.; Fatherree, J.P.; Cortez, E.; Li, C.; Bilton, S.; Timonina, D.; Myers, D.T.; Lee, D.; Gomez-Caraballo, M.; Greenberg, M.; Nangia, V.; Greninger, P.; Egan, R.K.; McClanaghan, J.; Stein, G.T.; Murchie, E.; Zarrinkar, P.P.; Janes, M.R.; Li, L.S.; Liu, Y.; Hata, A.N.; Benes, C.H. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin. Cancer Res., 2019, 25(2), 796-807.
[] [PMID: 30327306]
Xia, Y.; Liu, Y.L.; Xie, Y.; Zhu, W.; Guerra, F.; Shen, S.; Yeddula, N.; Fischer, W.; Low, W.; Zhou, X.; Zhang, Y.; Oldfield, E.; Verma, I.M. A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin. Sci. Transl. Med., 2014, 6(262, 263ra161)
[] [PMID: 25411474]
Kang, Y.W.; Lee, J.E.; Jung, K.H.; Son, M.K.; Shin, S.M.; Kim, S.J.; Fang, Z.; Yan, H.H.; Park, J.H.; Han, B.; Cheon, M.J.; Woo, M.G.; Lim, J.H.; Kim, Y.S.; Hong, S.S. KRAS targeting antibody synergizes anti-cancer activity of gemcitabine against pancreatic cancer. Cancer Lett., 2018, 438, 174-186.
[] [PMID: 30217561]
Caiola, E.; Frapolli, R.; Tomanelli, M.; Valerio, R.; Iezzi, A.; Garassino, M.C.; Broggini, M.; Marabese, M. Wee1 inhibitor MK1775 sensitizes KRAS mutated NSCLC cells to sorafenib. Sci. Rep., 2018, 8(1), 948.
[] [PMID: 29343688]
Zhao, X.; Wang, X.; Fang, L.; Lan, C.; Zheng, X.; Wang, Y.; Zhang, Y.; Han, X.; Liu, S.; Cheng, K.; Zhao, Y.; Shi, J.; Guo, J.; Hao, J.; Ren, H.; Nie, G. A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS-mutant pancreatic cancer. Cancer Lett., 2017, 402, 61-70.
[] [PMID: 28576749]
Kitai, H.; Ebi, H.; Tomida, S.; Floros, K.V.; Kotani, H.; Adachi, Y.; Oizumi, S.; Nishimura, M.; Faber, A.C.; Yano, S. Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer. Cancer Discov., 2016, 6(7), 754-769.
[] [PMID: 27154822]
Pettazzoni, P.; Viale, A.; Shah, P.; Carugo, A.; Ying, H.; Wang, H.; Genovese, G.; Seth, S.; Minelli, R.; Green, T.; Huang-Hobbs, E.; Corti, D.; Sanchez, N.; Nezi, L.; Marchesini, M.; Kapoor, A.; Yao, W.; Francesco, M.E.; Petrocchi, A.; Deem, A.K.; Scott, K.; Colla, S.; Mills, G.B.; Fleming, J.B.; Heffernan, T.P.; Jones, P.; Toniatti, C.; DePinho, R.A.; Draetta, G.F. Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. Cancer Res., 2015, 75(6), 1091-1101.
[] [PMID: 25736685]
Manchado, E.; Weissmueller, S.; Morris, J.P., IV; Chen, C.C.; Wullenkord, R.; Lujambio, A.; de Stanchina, E.; Poirier, J.T.; Gainor, J.F.; Corcoran, R.B.; Engelman, J.A.; Rudin, C.M.; Rosen, N.; Lowe, S.W. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature, 2016, 534(7609), 647-651.
[] [PMID: 27338794]
Kruspig, B.; Monteverde, T.; Neidler, S.; Hock, A.; Kerr, E.; Nixon, C.; Clark, W.; Hedley, A.; Laing, S.; Coffelt, S.B.; Le Quesne, J.; Dick, C.; Vousden, K.H.; Martins, C.P.; Murphy, D.J. The ERBB network facilitates KRAS-driven lung tumorigenesis. Sci. Transl. Med., 2018, 10(446), pii eaao2565.
[] [PMID: 29925636]
Sun, C.; Hobor, S.; Bertotti, A.; Zecchin, D.; Huang, S.; Galimi, F.; Cottino, F.; Prahallad, A.; Grernrum, W.; Tzani, A.; Schlicker, A.; Wessels, L.F.; Smit, E.F.; Thunnissen, E.; Halonen, P.; Lieftink, C.; Beijersbergen, R.L.; Di Nicolantonio, F.; Bardelli, A.; Trusolino, L.; Bernards, R. Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Rep., 2014, 7(1), 86-93.
[] [PMID: 24685132]
Suzawa, K.; Offin, M.; Lu, D.; Kurzatkowski, C.; Vojnic, M.; Smith, R.S.; Sabari, J.K.; Tai, H.; Mattar, M.; Khodos, I.; de Stanchina, E.; Rudin, C.M.; Kris, M.G.; Arcila, M.E.; Lockwood, W.W.; Drilon, A.; Ladanyi, M.; Somwar, R. Activation of KRAS mediates resistance to targeted therapy in MET Exon 14-mutant non-small cell lung cancer. Clin. Cancer Res., 2019, 25(4), 1248-1260.
[] [PMID: 30352902]
Lamba, S.; Russo, M.; Sun, C.; Lazzari, L.; Cancelliere, C.; Grernrum, W.; Lieftink, C.; Bernards, R.; Di Nicolantonio, F.; Bardelli, A. RAF suppression synergizes with MEK inhibition in KRAS mutant cancer cells. Cell Rep., 2014, 8(5), 1475-1483.
[] [PMID: 25199829]
Dompe, N.; Klijn, C.; Watson, S.A.; Leng, K.; Port, J.; Cuellar, T.; Watanabe, C.; Haley, B.; Neve, R.; Evangelista, M.; Stokoe, D. A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC. PLoS One, 2018, 13(6)e0199264
[] [PMID: 29912950]
Kuracha, M.R.; Thomas, P.; Loggie, B.W.; Govindarajan, V. Bilateral blockade of MEK- and PI3K-mediated pathways downstream of mutant KRAS as a treatment approach for peritoneal mucinous malignancies. PLoS One, 2017, 12(6)e0179510
[] [PMID: 28640835]
De Roock, W.; Jonker, D.J.; Di Nicolantonio, F.; Sartore-Bianchi, A.; Tu, D.; Siena, S.; Lamba, S.; Arena, S.; Frattini, M.; Piessevaux, H.; Van Cutsem, E.; O’Callaghan, C.J.; Khambata-Ford, S.; Zalcberg, J.R.; Simes, J.; Karapetis, C.S.; Bardelli, A.; Tejpar, S. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA, 2010, 304(16), 1812-1820.
[ 10.1001/jama.2010.1535]
Chen, R.; Sweet-Cordero, E.A. Two is better than one: combining IGF1R and MEK blockade as a promising novel treatment strategy against KRAS-mutant lung cancer. Cancer Discov., 2013, 3(5), 491-493.
[] [PMID: 23658296]
Park, K.S.; Oh, B.; Lee, M.H.; Nam, K.Y.; Jin, H.R.; Yang, H.; Choi, J.; Kim, S.W.; Lee, D.H. The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib. Cancer Lett., 2016, 372(1), 75-81.
[] [PMID: 26723875]
Zhu, Z.; Aref, A.R.; Cohoon, T.J.; Barbie, T.U.; Imamura, Y.; Yang, S.; Moody, S.E.; Shen, R.R.; Schinzel, A.C.; Thai, T.C.; Reibel, J.B.; Tamayo, P.; Godfrey, J.T.; Qian, Z.R.; Page, A.N.; Maciag, K.; Chan, E.M.; Silkworth, W.; Labowsky, M.T.; Rozhansky, L.; Mesirov, J.P.; Gillanders, W.E.; Ogino, S.; Hacohen, N.; Gaudet, S.; Eck, M.J.; Engelman, J.A.; Corcoran, R.B.; Wong, K.K.; Hahn, W.C.; Barbie, D.A. Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov., 2014, 4(4), 452-465.
[] [PMID: 24444711]
Zhao, C.; Xiao, H.; Wu, X.; Li, C.; Liang, G.; Yang, S.; Lin, J. Rational combination of MEK inhibitor and the STAT3 pathway modulator for the therapy in K-Ras mutated pancreatic and colon cancer cells. Oncotarget, 2015, 6(16), 14472-14487.
[] [PMID: 25961376]
Pek, M.; Yatim, S.M.J.M.; Chen, Y.; Li, J.; Gong, M.; Jiang, X.; Zhang, F.; Zheng, J.; Wu, X.; Yu, Q. Oncogenic KRAS-associated gene signature defines co-targeting of CDK4/6 and MEK as a viable therapeutic strategy in colorectal cancer. Oncogene, 2017, 36(35), 4975-4986.
[] [PMID: 28459468]
Davis, S.L.; Robertson, K.M.; Pitts, T.M.; Tentler, J.J.; Bradshaw-Pierce, E.L.; Klauck, P.J.; Bagby, S.M.; Hyatt, S.L.; Selby, H.M.; Spreafico, A.; Ecsedy, J.A.; Arcaroli, J.J.; Messersmith, W.A.; Tan, A.C.; Eckhardt, S.G. Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models. Front. Pharmacol., 2015, 6, 120.
[] [PMID: 26136684]
Zaanan, A.; Okamoto, K.; Kawakami, H.; Khazaie, K.; Huang, S.; Sinicrope, F.A. The Mutant KRAS gene up-regulates BCL-XL Protein via STAT3 to confer apoptosis resistance that is reversed by bim protein induction and BCL-XL antagonism. J. Biol. Chem., 2015, 290(39), 23838-23849.
[] [PMID: 26245900]
Hata, A.N.; Rowley, S.; Archibald, H.L.; Gomez-Caraballo, M.; Siddiqui, F.M.; Ji, F.; Jung, J.; Light, M.; Lee, J.S.; Debussche, L.; Sidhu, S.; Sadreyev, R.I.; Watters, J.; Engelman, J.A. Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers. Oncogene, 2017, 36(47), 6581-6591.
[] [PMID: 28783173]
Yamada, T.; Amann, J.M.; Tanimoto, A.; Taniguchi, H.; Shukuya, T.; Timmers, C.; Yano, S.; Shilo, K.; Carbone, D.P. Histone deacetylase inhibition enhances the antitumor activity of a MEK inhibitor in lung cancer cells harboring RAS mutations. Mol. Cancer Ther., 2018, 17(1), 17-25.
[] [PMID: 29079711]
Kim, E.Y.; Kim, A.; Kim, S.K.; Chang, Y.S. AZD6244 inhibits cisplatin-induced ERK1/2 activation and potentiates cisplatin-associated cytotoxicity in K-ras G12D preclinical models. Cancer Lett., 2015, 358(1), 85-91.
[] [PMID: 25541062]
Toulany, M.; Minjgee, M.; Saki, M.; Holler, M.; Meier, F.; Eicheler, W.; Rodemann, H.P. ERK2-dependent reactivation of Akt mediates the limited response of tumor cells with constitutive K-RAS activity to PI3K inhibition. Cancer Biol. Ther., 2014, 15(3), 317-328.
[] [PMID: 24351425]
Park, K.S.; Yang, H.; Choi, J.; Seo, S.; Kim, D.; Lee, C.H.; Jeon, H.; Kim, S.W.; Lee, D.H. The HSP90 inhibitor, NVP-AUY922, attenuates intrinsic PI3K inhibitor resistance in KRAS-mutant non-small cell lung cancer. Cancer Lett., 2017, 406, 47-53.
[] [PMID: 28797845]
Song, Q.; Sun, X.; Guo, H.; Yu, Q. Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells. Oncotarget, 2017, 8(3), 5003-5015.
[] [PMID: 28002807]
Hu, C.; Dadon, T.; Chenna, V.; Yabuuchi, S.; Bannerji, R.; Booher, R.; Strack, P.; Azad, N.; Nelkin, B.D.; Maitra, A. Combined inhibition of cyclin-dependent kinases (Dinaciclib) and AKT (MK-2206) blocks pancreatic tumor growth and metastases in patient-derived xenograft models. Mol. Cancer Ther., 2015, 14(7), 1532-1539.
[] [PMID: 25931518]
Gulhati, P.; Zaytseva, Y.Y.; Valentino, J.D.; Stevens, P.D.; Kim, J.T.; Sasazuki, T.; Shirasawa, S.; Lee, E.Y.; Weiss, H.L.; Dong, J.; Gao, T.; Evers, B.M. Sorafenib enhances the therapeutic efficacy of rapamycin in colorectal cancers harboring oncogenic KRAS and PIK3CA. Carcinogenesis, 2012, 33(9), 1782-1790.
[] [PMID: 22696593]
Belmont, P.J.; Jiang, P.; McKee, T.D.; Xie, T.; Isaacson, J.; Baryla, N.E.; Roper, J.; Sinnamon, M.J.; Lee, N.V.; Kan, J.L.; Guicherit, O.; Wouters, B.G.; O’Brien, C.A.; Shields, D.; Olson, P.; VanArsdale, T.; Weinrich, S.L.; Rejto, P.; Christensen, J.G.; Fantin, V.R.; Hung, K.E.; Martin, E.S. Resistance to dual blockade of the kinases PI3K and mTOR in KRAS-mutant colorectal cancer models results in combined sensitivity to inhibition of the receptor tyrosine kinase EGFR. Sci. Signal., 2014, 7(351), ra107.
[] [PMID: 25389372]
Rajurkar, M.; Dang, K.; Fernandez-Barrena, M.G.; Liu, X.; Fernandez-Zapico, M.E.; Lewis, B.C.; Mao, J. IKBKE is required during KRAS-induced pancreatic tumorigenesis. Cancer Res., 2017, 77(2), 320-329.
[] [PMID: 28069799]
Malone, C.F.; Emerson, C.; Ingraham, R.; Barbosa, W.; Guerra, S.; Yoon, H.; Liu, L.L.; Michor, F.; Haigis, M.; Macleod, K.F.; Maertens, O.; Cichowski, K. mTOR and HDAC inhibitors converge on the TXNIP/Thioredoxin pathway to cause catastrophic oxidative stress and regression of RAS-driven tumors. Cancer Discov., 2017, 7(12), 1450-1463.
[] [PMID: 28963352]
Faber, A.C.; Coffee, E.M.; Costa, C.; Dastur, A.; Ebi, H.; Hata, A.N.; Yeo, A.T.; Edelman, E.J.; Song, Y.; Tam, A.T.; Boisvert, J.L.; Milano, R.J.; Roper, J.; Kodack, D.P.; Jain, R.K.; Corcoran, R.B.; Rivera, M.N.; Ramaswamy, S.; Hung, K.E.; Benes, C.H.; Engelman, J.A. mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1. Cancer Discov., 2014, 4(1), 42-52.
[] [PMID: 24163374]
Weisberg, E.; Nonami, A.; Chen, Z.; Liu, F.; Zhang, J.; Sattler, M.; Nelson, E.; Cowens, K.; Christie, A.L.; Mitsiades, C.; Wong, K.K.; Liu, Q.; Gray, N.; Griffin, J.D. Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies. Leukemia, 2015, 29(1), 27-37.
[] [PMID: 24791855]
Liang, S.Q.; Bührer, E.D.; Berezowska, S.; Marti, T.M.; Xu, D.; Froment, L.; Yang, H.; Hall, S.R.R.; Vassella, E.; Yang, Z.; Kocher, G.J.; Amrein, M.A.; Riether, C.; Ochsenbein, A.F.; Schmid, R.A.; Peng, R.W. mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer. Oncogene, 2019, 38(5), 622-636.
[] [PMID: 30171261]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 15 November, 2019
Page: [2081 - 2097]
Pages: 17
DOI: 10.2174/1568026619666190905164144
Price: $65

Article Metrics

PDF: 76
HTML: 16
PRC: 1