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Current Topics in Medicinal Chemistry


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

Review Article

Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Mutations in the Occurrence and Treatment of Pancreatic Cancer

Author(s): Ziying Zhu, Saisong Xiao, Haojie Hao*, Qian Hou* and Xiaobing Fu*

Volume 19 , Issue 23 , 2019

Page: [2176 - 2186] Pages: 11

DOI: 10.2174/1568026619666190828160804

Price: $65


Pancreatic cancer is a highly malignant tumor with a 5-year survival rate of less than 6%, and incidence increasing year by year globally. Pancreatic cancer has a poor prognosis and a high recurrence rate, almost the same as the death rate. However, the available effective prevention and treatment measures for pancreatic cancer are still limited. The genome variation is one of the main reasons for the development of pancreatic cancer. In recent years, with the development of gene sequencing technology, in-depth research on pancreatic cancer gene mutation presents that a growing number of genetic mutations are confirmed to be in a close relationship with invasion and metastasis of pancreatic cancer. Among them, KRAS mutation is a special one. Therefore, it is particularly important to understand the mechanism of the KRAS mutation in the occurrence and development of pancreatic cancer, and to explore the method of its transformation into clinical tumor molecular targeted treatment sites, to further improve the therapeutic effect on pancreatic cancer. Therefore, to better design chemical drugs, this review based on the biological functions of KRAS, summarized the types of KRAS mutations and their relationship with pancreatic cancer and included the downstream signaling pathway Raf-MEK-ERK, PI3K-AKT, RalGDS-Ral of KRAS and the current medicinal treatment methods for KRAS mutations. Moreover, drug screening and clinical treatment for KRAS mutated cell and animal models of pancreatic cancer are also reviewed along with the prospect of targeted medicinal chemistry therapy for precision treatment of pancreatic cancer in the future.

Keywords: Pancreatic cancer, Drug screening, KRAS mutations, Chemistry drugs, Precision treatment, Malignant tumor.

Graphical Abstract
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[] [PMID: 25220842]
Rahib, L.; Smith, B.D.; Aizenberg, R.; Rosenzweig, A.B.; Fleshman, J.M.; Matrisian, L.M. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res., 2014, 74(11), 2913-2921.
[] [PMID: 24840647]
Yang, G.Y.; Wagner, T.D.; Fuss, M.; Thomas, C.R. Jr. Multimodality approaches for pancreatic cancer. CA Cancer J. Clin., 2005, 55(6), 352-367.
[] [PMID: 16282280]
(a) Ihse, I.; Permert, J.; Andersson, R.; Borgstrom, A.; Dawiskiba, S.; Enander, L.K.; Glimelius, B.; Hafstrom, L.; Haglund, U.; Larsson, J.; Lindell, G.; Olmarker, A.; von Rosen, A.; Svanvik, J.; Svensson, J.O.; Thune, A.; Tranberg, K.G. Guidelines for management of patients with pancreatic cancer. Lakartidningen, 2002, 99(15), 1676-1680. 1683-1685.
(b) O’Reilly, E.M.; Abou-Alfa, G.K.; Shamseddine, A.; Skouri, H.; Tawil, A.; Eloubeidi, M.A.; Lowery, M.; Kharfan-Dabaja, M.; Kaprealian, T.; Temraz, S.; Sibai, H.; Farran, H.; Shah, M.A. Gastrointestinal cancer educational case series: management of metastatic adenocarcinoma of unknown primary origin in a Ph+ ALL survivor. J. Gastrointest. Cancer, 2011, 42(3), 165-170.
[PMID: 21128012]
Waddell, N.; Pajic, M.; Patch, A.M.; Chang, D.K.; Kassahn, K.S.; Bailey, P.; Johns, A.L.; Miller, D.; Nones, K.; Quek, K.; Quinn, M.C.; Robertson, A.J.; Fadlullah, M.Z.; Bruxner, T.J.; Christ, A.N.; Harliwong, I.; Idrisoglu, S.; Manning, S.; Nourse, C.; Nourbakhsh, E.; Wani, S.; Wilson, P.J.; Markham, E.; Cloonan, N.; Anderson, M.J.; Fink, J.L.; Holmes, O.; Kazakoff, S.H.; Leonard, C.; Newell, F.; Poudel, B.; Song, S.; Taylor, D.; Waddell, N.; Wood, S.; Xu, Q.; Wu, J.; Pinese, M.; Cowley, M.J.; Lee, H.C.; Jones, M.D.; Nagrial, A.M.; Humphris, J.; Chantrill, L.A.; Chin, V.; Steinmann, A.M.; Mawson, A.; Humphrey, E.S.; Colvin, E.K.; Chou, A.; Scarlett, C.J.; Pinho, A.V.; Giry-Laterriere, M.; Rooman, I.; Samra, J.S.; Kench, J.G.; Pettitt, J.A.; Merrett, N.D.; Toon, C.; Epari, K.; Nguyen, N.Q.; Barbour, A.; Zeps, N.; Jamieson, N.B.; Graham, J.S.; Niclou, S.P.; Bjerkvig, R.; Grützmann, R.; Aust, D.; Hruban, R.H.; Maitra, A.; Iacobuzio-Donahue, C.A.; Wolfgang, C.L.; Morgan, R.A.; Lawlor, R.T.; Corbo, V.; Bassi, C.; Falconi, M.; Zamboni, G.; Tortora, G.; Tempero, M.A.; Gill, A.J.; Eshleman, J.R.; Pilarsky, C.; Scarpa, A.; Musgrove, E.A.; Pearson, J.V.; Biankin, A.V.; Grimmond, S.M. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature, 2015, 518(7540), 495-501.
[] [PMID: 25719666]
Cancer Genome Atlas Research Network. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell, 2017, 32(2), 185-203.
(a) Yachida, S.; Jones, S.; Bozic, I.; Antal, T.; Leary, R.; Fu, B.; Kamiyama, M.; Hruban, R.H.; Eshleman, J.R.; Nowak, M.A.; Velculescu, V.E.; Kinzler, K.W.; Vogelstein, B.; Iacobuzio-Donahue, C.A. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature, 2010, 467(7319), 1114-1117.
(b) Yachida, S.; White, C.M.; Naito, Y.; Zhong, Y.; Brosnan, J.A.; Macgregor-Das, A.M.; Morgan, R.A.; Saunders, T.; Laheru, D.A.; Herman, J.M.; Hruban, R.H.; Klein, A.P.; Jones, S.; Velculescu, V.; Wolfgang, C.L.; Iacobuzio-Donahue, C.A. Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin. Cancer Res., 2012, 18(22), 6339-6347.
[] [PMID: 22991414]
Aung, K.L.; Fischer, S.E.; Denroche, R.E.; Jang, G.H.; Dodd, A.; Creighton, S.; Southwood, B.; Liang, S.B.; Chadwick, D.; Zhang, A.; O’Kane, G.M.; Albaba, H.; Moura, S.; Grant, R.C.; Miller, J.K.; Mbabaali, F.; Pasternack, D.; Lungu, I.M.; Bartlett, J.M.S.; Ghai, S.; Lemire, M.; Holter, S.; Connor, A.A.; Moffitt, R.A.; Yeh, J.J.; Timms, L.; Krzyzanowski, P.M.; Dhani, N.; Hedley, D.; Notta, F.; Wilson, J.M.; Moore, M.J.; Gallinger, S.; Knox, J.J. Genomics-driven precision medicine for advanced pancreatic cancer: early results from the COMPASS trial. Clin. Cancer Res., 2018, 24(6), 1344-1354.
[] [PMID: 29288237]
Graham, J.S.; Jamieson, N.B.; Rulach, R.; Grimmond, S.M.; Chang, D.K.; Biankin, A.V. Pancreatic cancer genomics: where can the science take us? Clin. Genet., 2015, 88(3), 213-219.
[] [PMID: 25388820]
(a) Hata, A.N.; Yeo, A.; Faber, A.C.; Lifshits, E.; Chen, Z.; Cheng, K.A.; Walton, Z.; Sarosiek, K.A.; Letai, A.; Heist, R.S.; Mino-Kenudson, M.; Wong, K.K.; Engelman, J.A. Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS-mutant lung cancers. Cancer Res., 2014, 74(11), 3146-3156.
(b) Hosoda, W.; Chianchiano, P.; Griffin, J.F.; Pittman, M.E.; Brosens, L.A.; Noe, M.; Yu, J.; Shindo, K.; Suenaga, M.; Rezaee, N.; Yonescu, R.; Ning, Y.; Albores-Saavedra, J.; Yoshizawa, N.; Harada, K.; Yoshizawa, A.; Hanada, K.; Yonehara, S.; Shimizu, M.; Uehara, T.; Samra, J.S.; Gill, A.J.; Wolfgang, C.L.; Goggins, M.G.; Hruban, R.H.; Wood, L.D. Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4. J. Pathol., 2017, 242(1), 16-23.
[PMID: 28188630]
di Magliano, M.P.; Logsdon, C.D. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology, 2013, 144(6), 1220-1229.
[] [PMID: 23622131]
(a) Eickhoff, A.; Martin, W.; Hartmann, D.; Eickhoff, J.C.; Mohler, M.; Galle, P.R.; Riemann, J.F.; Jakobs, R. A phase I/II multicentric trial of gemcitabine and epirubicin in patients with advanced pancreatic carcinoma. Br. J. Cancer, 2006, 94(11), 1572-1574.
(b) Gold, D.V.; Lew, K.; Maliniak, R.; Hernandez, M.; Cardillo, T. Characterization of monoclonal antibody PAM4 reactive with a pancreatic cancer mucin. Int. J. Cancer, 1994, 57(2), 204-210.
[PMID: 7512537]
(a) Bhirde, A.A.; Patel, V.; Gavard, J.; Zhang, G.; Sousa, A.A.; Masedunskas, A.; Leapman, R.D.; Weigert, R.; Gutkind, J.S.; Rusling, J.F. Targeted killing of cancer cells in vivo and in vitro with EGF-directed carbon nanotube-based drug delivery. ACS Nano, 2009, 3(2), 307-316.
(b) Calixto, G.M.; Bernegossi, J.; de Freitas, L.M.; Fontana, C.R.; Chorilli, M. Nanotechnology-Based Drug Delivery Systems for Photodynamic Therapy of Cancer: A Review. Molecules, 2016, 21(3), 342.
(c) Fischer, A.; Wu, S.; Ho, A.L.; Lacouture, M.E. The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and meta-analysis. Invest. New Drugs, 2013, 31(3), 787-797.
(d) Majhi, M.; Ali, M.A.; Limaye, A.; Sinha, K.; Bairagi, P.; Chouksey, M.; Shukla, R.; Kanwar, N.; Hussain, T.; Nayarisseri, A.; Singh, S.K. An In Silico Investigation of Potential EGFR Inhibitors for the Clinical Treatment of Colorectal Cancer. Curr. Top. Med. Chem., 2018, 18(27), 2355-2366.
(e) Zhong, H.; Bowen, J.P. Recent advances in small molecule inhibitors of VEGFR and EGFR signaling pathways. Curr. Top. Med. Chem., 2011, 11(12), 1571-1590.
[PMID: 21510831]
Farooq, M.A.; Aquib, M.; Farooq, A.; Haleem Khan, D.; Joelle Maviah, M.B.; Sied Filli, M.; Kesse, S.; Boakye-Yiadom, K.O.; Mavlyanova, R.; Parveen, A.; Wang, B. Recent progress in nanotechnology-based novel drug delivery systems in designing of cisplatin for cancer therapy: an overview. Artif. Cells Nanomed. Biotechnol., 2019, 47(1), 1674-1692.
[] [PMID: 31066300]
Drilon, A.; Rekhtman, N.; Ladanyi, M.; Paik, P. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol., 2012, 13(10), e418-e426.
[] [PMID: 23026827]
Santos, E.; Martin-Zanca, D.; Reddy, E.P.; Pierotti, M.A.; Della Porta, G.; Barbacid, M. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science, 1984, 223(4637), 661-664.
[] [PMID: 6695174]
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.
[] [PMID: 25561545]
O’Bryan, J.P. Pharmacological targeting of RAS: recent success with direct inhibitors. Pharmacol. Res., 2019, 139, 503-511.
[] [PMID: 30366101]
(a) Lavoie, H.; Therrien, M. Regulation of RAF protein kinases in ERK signalling. Nat. Rev. Mol. Cell Biol., 2015, 16(5), 281-298.
(b) Ritt, D.A.; Abreu-Blanco, M.T.; Bindu, L.; Durrant, D.E.; Zhou, M.; Specht, S.I.; Stephen, A.G.; Holderfield, M.; Morrison, D.K. Inhibition of Ras/Raf/MEK/ERK pathway signaling by a stress-induced phospho-regulatory circuit. Mol. Cell, 2016, 64(5), 875-887.
(c) Roskoski, R., Jr Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol. Res., 2018, 135, 239-258.
(d) Wallace, E.M.; Lyssikatos, J.P.; Yeh, T.; Winkler, J.D.; Koch, K. Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. Curr. Top. Med. Chem., 2005, 5(2), 215-229.
(e) Wang, J.Y.; Wilcoxen, K.M.; Nomoto, K.; Wu, S. Recent advances of MEK inhibitors and their clinical progress. Curr. Top. Med. Chem., 2007, 7(14), 1364-1378.
[PMID: 17692026]
Gysin, S.; Lee, S.H.; Dean, N.M.; McMahon, M. Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res., 2005, 65(11), 4870-4880.
[] [PMID: 15930308]
Campbell, P.M.; Groehler, A.L.; Lee, K.M.; Ouellette, M.M.; Khazak, V.; Der, C.J. K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by Raf and phosphatidylinositol 3-kinase signaling. Cancer Res., 2007, 67(5), 2098-2106.
[] [PMID: 17332339]
Collisson, E.A.; Trejo, C.L.; Silva, J.M.; Gu, S.; Korkola, J.E.; Heiser, L.M.; Charles, R.P.; Rabinovich, B.A.; Hann, B.; Dankort, D.; Spellman, P.T.; Phillips, W.A.; Gray, J.W.; McMahon, M. A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov., 2012, 2(8), 685-693.
[] [PMID: 22628411]
(a) Delsin, L.E.A.; Salomao, K.B.; Pezuk, J.A.; Brassesco, M.S. Expression profiles and prognostic value of miRNAs in retinoblastoma. J. Cancer Res. Clin. Oncol., 2019, 145(1), 1-10.
(b) Gasparri, M.L.; Besharat, Z.M.; Farooqi, A.A.; Khalid, S.; Taghavi, K.; Besharat, R.A.; Sabato, C.; Papadia, A.; Panici, P.B.; Mueller, M.D.; Ferretti, E. MiRNAs and their interplay with PI3K/AKT/mTOR pathway in ovarian cancer cells: a potential role in platinum resistance. J. Cancer Res. Clin. Oncol., 2018, 144(12), 2313-2318.
[PMID: 30109500]
Papadimitrakopoulou, V. Development of PI3K/AKT/mTOR pathway inhibitors and their application in personalized therapy for non-small-cell lung cancer. J. Thorac. Oncol., 2012, 7(8), 1315-1326.
[] [PMID: 22648207]
(a) Baer, R.; Cintas, C.; Therville, N.; Guillermet-Guibert, J. Implication of PI3K/Akt pathway in pancreatic cancer: When PI3K isoforms matter? Adv. Biol. Regul., 2015, 59, 19-35.
(b) Sabbah, D.A.; Hu, J.; Zhong, H.A. Advances in the Development of Class I Phosphoinositide 3-Kinase (PI3K) Inhibitors. Curr. Top. Med. Chem., 2016, 16(13), 1413-1426.
[PMID: 26369826]
Eser, S.; Reiff, N.; Messer, M.; Seidler, B.; Gottschalk, K.; Dobler, M.; Hieber, M.; Arbeiter, A.; Klein, S.; Kong, B.; Michalski, C.W.; Schlitter, A.M.; Esposito, I.; Kind, A.J.; Rad, L.; Schnieke, A.E.; Baccarini, M.; Alessi, D.R.; Rad, R.; Schmid, R.M.; Schneider, G.; Saur, D. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell, 2013, 23(3), 406-420.
[] [PMID: 23453624]
Mao, Y.; Xi, L.; Li, Q.; Cai, Z.; Lai, Y.; Zhang, X.; Yu, C. Regulation of cell apoptosis and proliferation in pancreatic cancer through PI3K/Akt pathway via Polo-like kinase 1. Oncol. Rep., 2016, 36(1), 49-56.
[] [PMID: 27220401]
Yao, R.; Xu, L.; Wei, B.; Qian, Z.; Wang, J.; Hui, H.; Sun, Y. miR-142-5p regulates pancreatic cancer cell proliferation and apoptosis by regulation of RAP1A. Pathol. Res. Pract., 2019, 215(6)152416
[] [PMID: 31047726]
Yoshizawa, R.; Umeki, N.; Yanagawa, M.; Murata, M.; Sako, Y. Single-molecule fluorescence imaging of RalGDS on cell surfaces during signal transduction from Ras to Ral. Biophys. Physicobiol., 2017, 14, 75-84.
[] [PMID: 28744424]
Kashatus, D.F. Ral GTPases in tumorigenesis: emerging from the shadows. Exp. Cell Res., 2013, 319(15), 2337-2342.
[] [PMID: 23830877]
Guin, S.; Ru, Y.; Wynes, M.W.; Mishra, R.; Lu, X.; Owens, C.; Barn, A.E.; Vasu, V.T.; Hirsch, F.R.; Kern, J.A.; Theodorescu, D. Contributions of KRAS and RAL in non-small-cell lung cancer growth and progression. J. Thorac. Oncol., 2013, 8(12), 1492-1501.
[] [PMID: 24389431]
Lim, K.H.; Baines, A.T.; Fiordalisi, J.J.; Shipitsin, M.; Feig, L.A.; Cox, A.D.; Der, C.J.; Counter, C.M. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell, 2005, 7(6), 533-545.
[] [PMID: 15950903]
(a) Shepherd, F.A.; Domerg, C.; Hainaut, P.; Janne, P.A.; Pignon, J.P.; Graziano, S.; Douillard, J.Y.; Brambilla, E.; Le Chevalier, T.; Seymour, L.; Bourredjem, A.; Le Teuff, G.; Pirker, R.; Filipits, M.; Rosell, R.; Kratzke, R.; Bandarchi, B.; Ma, X.; Capelletti, M.; Soria, J.C.; Tsao, M.S. Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J. Clin. Oncol., 2013, 31(17), 2173-2181.
(b) Shepherd, F.A.; Lacas, B.; Le Teuff, G.; Hainaut, P.; Janne, P.A.; Pignon, J.P.; Le Chevalier, T.; Seymour, L.; Douillard, J.Y.; Graziano, S.; Brambilla, E.; Pirker, R.; Filipits, M.; Kratzke, R.; Soria, J.C.; Tsao, M.S. Group, L.A.-B.C., Pooled analysis of the prognostic and predictive effects of tp53 comutation status combined with KRAS or EGFR mutation in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J. Clin. Oncol., 2017, 35(18), 2018-2027.
(c) Tomasini, P.; Walia, P.; Labbe, C.; Jao, K.; Leighl, N.B. Targeting the KRAS pathway in non-small cell lung cancer. Oncologist, 2016, 21(12), 1450-1460.
[PMID: 27807303]
Riely, G.J.; Kris, M.G.; Rosenbaum, D.; Marks, J.; Li, A.; Chitale, D.A.; Nafa, K.; Riedel, E.R.; Hsu, M.; Pao, W.; Miller, V.A.; Ladanyi, M. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin. Cancer Res., 2008, 14(18), 5731-5734.
[] [PMID: 18794081]
Li, M.; Liu, L.; Liu, Z.; Yue, S.; Zhou, L.; Zhang, Q.; Cheng, S.; Li, R.W.; Smith, P.N.; Lu, S. The status of KRAS mutations in patients with non-small cell lung cancers from mainland China. Oncol. Rep., 2009, 22(5), 1013-1020.
[PMID: 19787214]
Ihle, N.T.; Byers, L.A.; Kim, E.S.; Saintigny, P.; Lee, J.J.; Blumenschein, G.R.; Tsao, A.; Liu, S.; Larsen, J.E.; Wang, J.; Diao, L.; Coombes, K.R.; Chen, L.; Zhang, S.; Abdelmelek, M.F.; Tang, X.; Papadimitrakopoulou, V.; Minna, J.D.; Lippman, S.M.; Hong, W.K.; Herbst, R.S.; Wistuba, I.I.; Heymach, J.V.; Powis, G. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J. Natl. Cancer Inst., 2012, 104(3), 228-239.
[] [PMID: 22247021]
Zhao, N.; Wilkerson, M.D.; Shah, U.; Yin, X.; Wang, A.; Hayward, M.C.; Roberts, P.; Lee, C.B.; Parsons, A.M.; Thorne, L.B.; Haithcock, B.E.; Grilley-Olson, J.E.; Stinchcombe, T.E.; Funkhouser, W.K.; Wong, K.K.; Sharpless, N.E.; Hayes, D.N. Alterations of LKB1 and KRAS and risk of brain metastasis: comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma. Lung Cancer, 2014, 86(2), 255-261.
[] [PMID: 25224251]
Bournet, B.; Buscail, C.; Muscari, F.; Cordelier, P.; Buscail, L. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities. Eur. J. Cancer, 2016, 54, 75-83.
[] [PMID: 26735353]
Qiu, W.; Tang, S.M.; Lee, S.; Turk, A.T.; Sireci, A.N.; Qiu, A.; Rose, C.; Xie, C.; Kitajewski, J.; Wen, H.J.; Crawford, H.C.; Sims, P.A.; Hruban, R.H.; Remotti, H.E.; Su, G.H. Loss of activin receptor type 1B accelerates development of intraductal papillary mucinous neoplasms in mice with activated KRAS. Gastroenterology, 2016, 150(1), 218-228. e12
Huang, H.; Daniluk, J.; Liu, Y.; Chu, J.; Li, Z.; Ji, B.; Logsdon, C.D. Oncogenic K-Ras requires activation for enhanced activity. Oncogene, 2014, 33(4), 532-535.
[] [PMID: 23334325]
(a) Notta, F.; Chan-Seng-Yue, M.; Lemire, M.; Li, Y.; Wilson, G.W.; Connor, A.A.; Denroche, R.E.; Liang, S.B.; Brown, A.M.; Kim, J.C.; Wang, T.; Simpson, J.T.; Beck, T.; Borgida, A.; Buchner, N.; Chadwick, D.; Hafezi-Bakhtiari, S.; Dick, J.E.; Heisler, L.; Hollingsworth, M.A.; Ibrahimov, E.; Jang, G.H.; Johns, J.; Jorgensen, L.G.; Law, C.; Ludkovski, O.; Lungu, I.; Ng, K.; Pasternack, D.; Petersen, G.M.; Shlush, L.I.; Timms, L.; Tsao, M.S.; Wilson, J.M.; Yung, C.K.; Zogopoulos, G.; Bartlett, J.M.; Alexandrov, L.B.; Real, F.X.; Cleary, S.P.; Roehrl, M.H.; McPherson, J.D.; Stein, L.D.; Hudson, T.J.; Campbell, P.J.; Gallinger, S. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature, 2016, 538(7625), 378-382.
(b) Notta, F.; Chan-Seng-Yue, M.; Lemire, M.; Li, Y.; Wilson, G.W.; Connor, A.A.; Denroche, R.E.; Liang, S.B.; Brown, A.M.; Kim, J.C.; Wang, T.; Simpson, J.T.; Beck, T.; Borgida, A.; Buchner, N.; Chadwick, D.; Hafezi-Bakhtiari, S.; Dick, J.E.; Heisler, L.; Hollingsworth, M.A.; Ibrahimov, E.; Jang, G.H.; Johns, J.; Jorgensen, L.G.; Law, C.; Ludkovski, O.; Lungu, I.; Ng, K.; Pasternack, D.; Petersen, G.M.; Shlush, L.I.; Timms, L.; Tsao, M.S.; Wilson, J.M.; Yung, C.K.; Zogopoulos, G.; Bartlett, J.M.; Alexandrov, L.B.; Real, F.X.; Cleary, S.P.; Roehrl, M.H.; McPherson, J.D.; Stein, L.D.; Hudson, T.J.; Campbell, P.J.; Gallinger, S. Erratum: A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature, 2017, 542(7639), 124.
[] [PMID: 27851734]
Delpu, Y.; Hanoun, N.; Lulka, H.; Sicard, F.; Selves, J.; Buscail, L.; Torrisani, J.; Cordelier, P. Genetic and epigenetic alterations in pancreatic carcinogenesis. Curr. Genomics, 2011, 12(1), 15-24.
[] [PMID: 21886451]
Blackford, A.; Serrano, O.K.; Wolfgang, C.L.; Parmigiani, G.; Jones, S.; Zhang, X.; Parsons, D.W.; Lin, J.C.; Leary, R.J.; Eshleman, J.R.; Goggins, M.; Jaffee, E.M.; Iacobuzio-Donahue, C.A.; Maitra, A.; Cameron, J.L.; Olino, K.; Schulick, R.; Winter, J.; Herman, J.M.; Laheru, D.; Klein, A.P.; Vogelstein, B.; Kinzler, K.W.; Velculescu, V.E.; Hruban, R.H. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin. Cancer Res., 2009, 15(14), 4674-4679.
[] [PMID: 19584151]
Windon, A.L.; Loaiza-Bonilla, A.; Jensen, C.E.; Randall, M.; Morrissette, J.J.D.; Shroff, S.G.A. KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma. J. Gastrointest. Oncol., 2018, 9(1), 1-10.
[] [PMID: 29564165]
Chen, H.; Tu, H.; Meng, Z.Q.; Chen, Z.; Wang, P.; Liu, L.M. K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer. Eur. J. Surg. Oncol., 2010, 36(7), 657-662.
[] [PMID: 20542658]
Golan, T.; Atias, D.; Barshack, I.; Avivi, C.; Goldstein, R.S.; Berger, R. Ascites-derived pancreatic ductal adenocarcinoma primary cell cultures as a platform for personalised medicine. Br. J. Cancer, 2014, 110(9), 2269-2276.
[] [PMID: 24667644]
(a) McFadden, D.G.; Politi, K.; Bhutkar, A.; Chen, F.K.; Song, X.; Pirun, M.; Santiago, P.M.; Kim-Kiselak, C.; Platt, J.T.; Lee, E.; Hodges, E.; Rosebrock, A.P.; Bronson, R.T.; Socci, N.D.; Hannon, G.J.; Jacks, T.; Varmus, H. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma. Proc. Natl. Acad. Sci. USA, 2016, 113(42), E6409-E6417.
(b) Oshima, K.; Khiabanian, H.; da Silva-Almeida, A.C.; Tzoneva, G.; Abate, F.; Ambesi-Impiombato, A.; Sanchez-Martin, M.; Carpenter, Z.; Penson, A.; Perez-Garcia, A.; Eckert, C.; Nicolas, C.; Balbin, M.; Sulis, M.L.; Kato, M.; Koh, K.; Paganin, M.; Basso, G.; Gastier-Foster, J.M.; Devidas, M.; Loh, M.L.; Kirschner-Schwabe, R.; Palomero, T.; Rabadan, R.; Ferrando, A.A. Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA, 2016, 113(40), 11306-11311.
[PMID: 27655895]
Platt, R.J.; Chen, S.; Zhou, Y.; Yim, M.J.; Swiech, L.; Kempton, H.R.; Dahlman, J.E.; Parnas, O.; Eisenhaure, T.M.; Jovanovic, M.; Graham, D.B.; Jhunjhunwala, S.; Heidenreich, M.; Xavier, R.J.; Langer, R.; Anderson, D.G.; Hacohen, N.; Regev, A.; Feng, G.; Sharp, P.A.; Zhang, F. CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell, 2014, 159(2), 440-455.
[] [PMID: 25263330]
Cicenas, J.; Kvederaviciute, K.; Meskinyte, I.; Meskinyte-Kausiliene, E.; Skeberdyte, A.; Cicenas, J. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer. Cancers (Basel), 2017, 9(5)E42
[] [PMID: 28452926]
Mellby, L.D.; Nyberg, A.P.; Johansen, J.S.; Wingren, C.; Nordestgaard, B.G.; Bojesen, S.E.; Mitchell, B.L.; Sheppard, B.C.; Sears, R.C.; Borrebaeck, C.A.K. Serum biomarker signature-based liquid biopsy for diagnosis of early-stage pancreatic cancer. J. Clin. Oncol., 2018, 36(28), 2887-2894.
[] [PMID: 30106639]
(a) Martins-Neves, S.R.; Cleton-Jansen, A.M.; Gomes, C.M.F. Therapy-induced enrichment of cancer stem-like cells in solid human tumors: where do we stand? Pharmacol. Res., 2018, 137, 193-204.
(b) Batra, H.; Pawar, S.; Bahl, D. Curcumin in combination with anti-cancer drugs: A nanomedicine review. Pharmacol. Res., 2019, 139, 91-105.
Lacal, P.M.; Graziani, G. Therapeutic implication of vascular endothelial growth factor receptor-1 (VEGFR-1) targeting in cancer cells and tumor microenvironment by competitive and non-competitive inhibitors. Pharmacol. Res., 2018, 136, 97-107.
[] [PMID: 30170190]
Roskoski, R., Jr Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacol. Res., 2019, 139, 395-411.
[] [PMID: 30500458]
Lee, J.; Jain, A.; Kim, P.; Lee, T.; Kuller, A.; Princen, F. In-GuDo, Kim, S.H.; Park, J.O.; Park, Y.S.; Singh, S.; Kim, H.C. Activated cMET and IGF1R-driven PI3K signaling predicts poor survival in colorectal cancers independent of KRAS mutational status. PLoS One, 2014, 9(8)e103551
[] [PMID: 25090459]
Gessi, S.; Merighi, S.; Stefanelli, A.; Fazzi, D.; Varani, K.; Borea, P.A.A. (1) and A(3) adenosine receptors inhibit LPS-induced hypoxia-inducible factor-1 accumulation in murine astrocytes. Pharmacol. Res., 2013, 76, 157-170.
[] [PMID: 23969284]
(a) Whittle, M.C.; Izeradjene, K.; Rani, P.G.; Feng, L.; Carlson, M.A.; DelGiorno, K.E.; Wood, L.D.; Goggins, M.; Hruban, R.H.; Chang, A.E.; Calses, P.; Thorsen, S.M.; Hingorani, S.R. RUNX3 Controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell, 2015, 161(6), 1345-1360.
(b) Roskoski, R., Jr Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas. Pharmacol. Res., 2017, 120, 116-132.
McCormick, F. K-Ras protein as a drug target. J. Mol. Med. (Berl.), 2016, 94(3), 253-258.
[] [PMID: 26960760]
Karoulia, Z.; Gavathiotis, E.; Poulikakos, P.I. New perspectives for targeting RAF kinase in human cancer. Nat. Rev. Cancer, 2017, 17(11), 676-691.
[] [PMID: 28984291]
Martin, S.; Dudek-Perić, A.M.; Maes, H.; Garg, A.D.; Gabrysiak, M.; Demirsoy, S.; Swinnen, J.V.; Agostinis, P. Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells. Biochem. Pharmacol., 2015, 93(3), 290-304.
[] [PMID: 25529535]
Peng, S.B.; Henry, J.R.; Kaufman, M.D.; Lu, W.P.; Smith, B.D.; Vogeti, S.; Rutkoski, T.J.; Wise, S.; Chun, L.; Zhang, Y.; Van Horn, R.D.; Yin, T.; Zhang, X.; Yadav, V.; Chen, S.H.; Gong, X.; Ma, X.; Webster, Y.; Buchanan, S.; Mochalkin, I.; Huber, L.; Kays, L.; Donoho, G.P.; Walgren, J.; McCann, D.; Patel, P.; Conti, I.; Plowman, G.D.; Starling, J.J.; Flynn, D.L. Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell, 2015, 28(3), 384-398.
[] [PMID: 26343583]
(a) 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.
(b) Cao, J.; Zhang, X.; Wang, Q.; Qiu, G.; Hou, C.; Wang, J.; Cheng, Q.; Lan, Y.; Han, H.; Shen, H.; Zhang, Y.; Yang, X.; Shen, B.; Zhang, J. Smad4 represses the generation of memory-precursor effector T cells but is required for the differentiation of central memory T cells. Cell Death Dis., 2015, 6e1984
Lee, S.H.; Jung, Y.S.; Chung, J.Y.; Oh, A.Y.; Lee, S.J.; Choi, D.H.; Jang, S.M.; Jang, K.S.; Paik, S.S.; Ha, N.C.; Park, B.J. Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1-PUMA pathway. Cell Death Dis., 2011, 2e235
[] [PMID: 22130069]
Du, X.; Pan, Z.; Li, Q.; Liu, H.; Li, Q. SMAD4 feedback regulates the canonical TGF-β signaling pathway to control granulosa cell apoptosis. Cell Death Dis., 2018, 9(2), 151.
[] [PMID: 29396446]
Zheng, L.; Jiao, W.; Song, H.; Qu, H.; Li, D.; Mei, H.; Chen, Y.; Yang, F.; Li, H.; Huang, K.; Tong, Q. miRNA-558 promotes gastric cancer progression through attenuating Smad4-mediated repression of heparanase expression. Cell Death Dis., 2016, 7(9)e2382
[] [PMID: 27685626]
Burmi, R.S.; Maginn, E.N.; Gabra, H.; Stronach, E.A.; Wasan, H.S. Combined inhibition of the PI3K/mTOR/MEK pathway induces Bim/Mcl-1-regulated apoptosis in pancreatic cancer cells. Cancer Biol. Ther., 2019, 20(1), 21-30.
[] [PMID: 30261145]
Mao, N.; Gao, D.; Hu, W.; Hieronymus, H.; Wang, S.; Lee, Y.S.; Lee, C.; Choi, D.; Gopalan, A.; Chen, Y.; Carver, B.S. Aberrant expression of ERG promotes resistance to combined PI3K and AR pathway inhibition through maintenance of AR target genes. Mol. Cancer Ther., 2019, 18, 1-10.
[] [PMID: 31296553]
Lopez, N.E.; Prendergast, C.; Lowy, A.M. Borderline resectable pancreatic cancer: Definitions and management. World J. Gastroenterol., 2014, 20(31), 10740-10751.
[] [PMID: 25152577]

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