Research progress on KRAS mutation in pancreatic tumorigenesis and pancreatic cancer therapy_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Fanghua ¹ , WU Yilin ² ,  GONG Jianping ²

1. Department of Surgery, Yubei District Second People’s Hospital of Chongqing City, Chongqing 401147, P. R. China;
2. Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P. R. China;

Corresponding author：

GONG Jianping, Email: gongjianping11@163.com

Keywords：

pancreatic cancer; KRAS mutation; molecular targeted therapy; review

DOI：

10.7507/1007-9424.201811069

Video：

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Objective To summarize the research progress of KRAS mutation in pancreatic tumorigenesis and therapy.Method The research progress of KRAS mutation in pancreatic tumorigenesis and therapy were summarized by reading the domestic and international literatures published in recent years.Results Pancreatic cancer had the title of " king of cancer”. More than 90% of pancreatic cancer patients had KRAS mutation. KRAS had a complex relationship with pancreatic cancer through downstream signaling pathways, including Raf (rapidly accelerated fibrosarcoma)-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK), phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT), and RalGDS-Ral. Although basic research on pancreatic cancer was deepening, there was still a lack of effective molecular targeted drugs.Conclusions KRASgene plays an important role in the occurrence of pancreatic cancer. The treatment associated with KRAS mutation provides a more effective prognostic possibility for pancreatic cancer patients.

Citation： WANG Fanghua, WU Yilin, GONG Jianping. Research progress on KRAS mutation in pancreatic tumorigenesis and pancreatic cancer therapy. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(6): 764-768. doi: 10.7507/1007-9424.201811069 Copy

1.	Chen W, Zheng R, Zhang S, et al. Cancer incidence and mortality in China in 2013: an analysis based on urbanization level. Chin J Cancer Res, 2017, 29(1): 1-10.
2.	Carrato A, Falcone A, Ducreux M, et al. A systematic review of the burden of pancreatic cancer in Europe: real-world impact on survival, quality of life and costs. J Gastrointest Cancer, 2015, 46(3): 201-211.
3.	Eser S, Schnieke A, Schneider G, et al. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer, 2014, 111(5): 817-822.
4.	Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell, 2017, 32(2): 185-203.
5.	Tsai FD, Lopes MS, Zhou M, et al. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proc Natl Acad Sci U S A, 2015, 112(3): 779-784.
6.	O’Bryan JP. Pharmacological targeting of RAS: recent success with direct inhibitors. Pharmacol Res, 2019, 139: 503-511.
7.	Kanda M, Matthaei H, Wu J, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology, 2012, 142(4): 730-733.
8.	Hashimoto D, Arima K, Yokoyama N, et al. Heterogeneity of KRAS mutations in pancreatic ductal adenocarcinoma. Pancreas, 2016, 45(8): 1111-1114.
9.	Brychta N, Krahn T, von Ahsen O. Detection of KRAS mutations in circulating tumor DNA by digital PCR in early stages of pancreatic cancer. Clin Chem, 2016, 62(11): 1482-1491.
10.	Gruber R, Panayiotou R, Nye E, et al. YAP1 and TAZ control pancreatic cancer initiation in mice by direct up-regulation of JAK-STAT3 signaling. Gastroenterology, 2016, 151(3): 526-539.
11.	Tao LY, Zhang LF, Xiu DR, et al. Prognostic significance of K-ras mutations in pancreatic cancer: a meta-analysis. World J Surg Oncol, 2016, 14: 146.
12.	Bournet B, Buscail C, Muscari F, et al. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: hopes and realities. Eur J Cancer, 2016, 54: 75-83.
13.	Qiu W, Tang SM, Lee S, et al. Loss of activin receptor type 1B accelerates development of intraductal papillary mucinous neoplasms in mice with activated KRAS. Gastroenterology, 2016, 150(1): 218-228.
14.	Huang H, Daniluk J, Liu Y, et al. Oncogenic K-Ras requires activation for enhanced activity. Oncogene, 2014, 33(4): 532-535.
15.	Roskoski R Jr. Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol Res, 2018, 135: 239-258.
16.	Ritt DA, Abreu-Blanco MT, Bindu L, et al. Inhibition of Ras/Raf/MEK/ERK pathway signaling by a stress-induced phospho-regulatory circuit. Mol Cell, 2016, 64(5): 875-887.
17.	Lavoie H, Therrien M. Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol, 2015, 16(5): 281-298.
18.	Gysin S, Lee SH, Dean NM, et al. 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.
19.	Campbell PM, Groehler AL, Lee KM, et al. 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.
20.	Collisson EA, Trejo CL, Silva JM, et al. A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov, 2012, 2(8): 685-693.
21.	Gasparri ML, Besharat ZM, Farooqi AA, et al. 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.
22.	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.
23.	Baer R, Cintas C, Therville N, et al. Implication of PI3K/Akt pathway in pancreatic cancer: when PI3K isoforms matter? Adv Biol Regul, 2015, 59: 19-35.
24.	Eser S, Reiff N, Messer M, et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell, 2013, 23(3): 406-420.
25.	Mao Y, Xi L, Li Q, et al. 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.
26.	Yoshizawa R, Umeki N, Yanagawa M, et al. Single-molecule fluorescence imaging of RalGDS on cell surfaces during signal transduction from Ras to Ral. Biophys Physicobiol, 2017, 14: 75-84.
27.	Kashatus DF. Ral GTPases in tumorigenesis: emerging from the shadows. Exp Cell Res, 2013, 319(15): 2337-2342.
28.	Guin S, Ru Y, Wynes MW, et al. Contributions of KRAS and RAL in non-small-cell lung cancer growth and progression. J Thorac Oncol, 2013, 8(12): 1492-1501.
29.	Lim KH, Baines AT, Fiordalisi JJ, et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell, 2005, 7(6): 533-545.
30.	Cicenas J, Kvederaviciute K, Meskinyte I, et al. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 mutations in pancreatic cancer. Cancers (Basel), 2017, 9(5): E42.
31.	Kamisawa T, Wood LD, Itoi T, et al. Pancreatic cancer. Lancet, 2016, 388(10039): 73-85.
32.	Mohammed S, Van Buren G 2^nd, Fisher WE. Pancreatic cancer: advances in treatment. World J Gastroenterol, 2014, 20(28): 9354-9360.
33.	Yuan TL, Fellmann C, Lee CS, et al. Development of siRNA payloads to target KRAS-mutant cancer. Cancer Discov, 2014, 4(10): 1182-1197.
34.	Kamerkar S, LeBleu VS, Sugimoto H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature, 2017, 546(7659): 498-503.
35.	McCormick F. K-Ras protein as a drug target. J Mol Med (Berl), 2016, 94(3): 253-258.
36.	Karoulia Z, Gavathiotis E, Poulikakos PI. New perspectives for targeting RAF kinase in human cancer. Nat Rev Cancer, 2017, 17(11): 676-691.
37.	Martin S, Dudek-Perić AM, Maes H, et al. 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.
38.	Peng SB, Henry JR, Kaufman MD, et al. 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.
39.	Zhao X, Wang X, Fang L, et al. A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS-mutant pancreatic cancer. Cancer Lett, 2017, 402: 61-70.
40.	Yen I, Shanahan F, Merchant M, et al. Pharmacological induction of RAS-GTP confers RAF inhibitor sensitivity in KRAS mutant tumors. Cancer Cell, 2018, 34(4): 611-625.
41.	Bodoky G, Timcheva C, Spigel DR, et al. A phase Ⅱ open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244[ARRY-142886] ) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs, 2012, 30(3): 1216-1223.
42.	Wang T, Wei J, Wang N, et al. The glucosylceramide synthase inhibitor PDMP sensitizes pancreatic cancer cells to MEK/ERK inhibitor AZD-6244. Biochem Biophys Res Commun, 2015, 456(3): 821-826.
43.	Burmi RS, Maginn EN, Gabra H, et al. 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.
44.	Kutkowska J, Strzadala L, Rapak A. Sorafenib in combination with betulinic acid synergistically induces cell cycle arrest and inhibits clonogenic activity in pancreatic ductal adenocarcinoma cells. Int J Mol Sci, 2018, 19(10): E3234.
45.	Lopez NE, Prendergast C, Lowy AM. Borderline resectable pancreatic cancer: definitions and management. World J Gastroenterol, 2014, 20(31): 10740-10751.

1. Chen W, Zheng R, Zhang S, et al. Cancer incidence and mortality in China in 2013: an analysis based on urbanization level. Chin J Cancer Res, 2017, 29(1): 1-10.
2. Carrato A, Falcone A, Ducreux M, et al. A systematic review of the burden of pancreatic cancer in Europe: real-world impact on survival, quality of life and costs. J Gastrointest Cancer, 2015, 46(3): 201-211.
3. Eser S, Schnieke A, Schneider G, et al. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer, 2014, 111(5): 817-822.
4. Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell, 2017, 32(2): 185-203.
5. Tsai FD, Lopes MS, Zhou M, et al. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proc Natl Acad Sci U S A, 2015, 112(3): 779-784.
6. O’Bryan JP. Pharmacological targeting of RAS: recent success with direct inhibitors. Pharmacol Res, 2019, 139: 503-511.
7. Kanda M, Matthaei H, Wu J, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology, 2012, 142(4): 730-733.
8. Hashimoto D, Arima K, Yokoyama N, et al. Heterogeneity of KRAS mutations in pancreatic ductal adenocarcinoma. Pancreas, 2016, 45(8): 1111-1114.
9. Brychta N, Krahn T, von Ahsen O. Detection of KRAS mutations in circulating tumor DNA by digital PCR in early stages of pancreatic cancer. Clin Chem, 2016, 62(11): 1482-1491.
10. Gruber R, Panayiotou R, Nye E, et al. YAP1 and TAZ control pancreatic cancer initiation in mice by direct up-regulation of JAK-STAT3 signaling. Gastroenterology, 2016, 151(3): 526-539.
11. Tao LY, Zhang LF, Xiu DR, et al. Prognostic significance of K-ras mutations in pancreatic cancer: a meta-analysis. World J Surg Oncol, 2016, 14: 146.
12. Bournet B, Buscail C, Muscari F, et al. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: hopes and realities. Eur J Cancer, 2016, 54: 75-83.
13. Qiu W, Tang SM, Lee S, et al. Loss of activin receptor type 1B accelerates development of intraductal papillary mucinous neoplasms in mice with activated KRAS. Gastroenterology, 2016, 150(1): 218-228.
14. Huang H, Daniluk J, Liu Y, et al. Oncogenic K-Ras requires activation for enhanced activity. Oncogene, 2014, 33(4): 532-535.
15. Roskoski R Jr. Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol Res, 2018, 135: 239-258.
16. Ritt DA, Abreu-Blanco MT, Bindu L, et al. Inhibition of Ras/Raf/MEK/ERK pathway signaling by a stress-induced phospho-regulatory circuit. Mol Cell, 2016, 64(5): 875-887.
17. Lavoie H, Therrien M. Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol, 2015, 16(5): 281-298.
18. Gysin S, Lee SH, Dean NM, et al. 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.
19. Campbell PM, Groehler AL, Lee KM, et al. 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.
20. Collisson EA, Trejo CL, Silva JM, et al. A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov, 2012, 2(8): 685-693.
21. Gasparri ML, Besharat ZM, Farooqi AA, et al. 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.
22. 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.
23. Baer R, Cintas C, Therville N, et al. Implication of PI3K/Akt pathway in pancreatic cancer: when PI3K isoforms matter? Adv Biol Regul, 2015, 59: 19-35.
24. Eser S, Reiff N, Messer M, et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell, 2013, 23(3): 406-420.
25. Mao Y, Xi L, Li Q, et al. 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.
26. Yoshizawa R, Umeki N, Yanagawa M, et al. Single-molecule fluorescence imaging of RalGDS on cell surfaces during signal transduction from Ras to Ral. Biophys Physicobiol, 2017, 14: 75-84.
27. Kashatus DF. Ral GTPases in tumorigenesis: emerging from the shadows. Exp Cell Res, 2013, 319(15): 2337-2342.
28. Guin S, Ru Y, Wynes MW, et al. Contributions of KRAS and RAL in non-small-cell lung cancer growth and progression. J Thorac Oncol, 2013, 8(12): 1492-1501.
29. Lim KH, Baines AT, Fiordalisi JJ, et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell, 2005, 7(6): 533-545.
30. Cicenas J, Kvederaviciute K, Meskinyte I, et al. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 mutations in pancreatic cancer. Cancers (Basel), 2017, 9(5): E42.
31. Kamisawa T, Wood LD, Itoi T, et al. Pancreatic cancer. Lancet, 2016, 388(10039): 73-85.
32. Mohammed S, Van Buren G 2^nd, Fisher WE. Pancreatic cancer: advances in treatment. World J Gastroenterol, 2014, 20(28): 9354-9360.
33. Yuan TL, Fellmann C, Lee CS, et al. Development of siRNA payloads to target KRAS-mutant cancer. Cancer Discov, 2014, 4(10): 1182-1197.
34. Kamerkar S, LeBleu VS, Sugimoto H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature, 2017, 546(7659): 498-503.
35. McCormick F. K-Ras protein as a drug target. J Mol Med (Berl), 2016, 94(3): 253-258.
36. Karoulia Z, Gavathiotis E, Poulikakos PI. New perspectives for targeting RAF kinase in human cancer. Nat Rev Cancer, 2017, 17(11): 676-691.
37. Martin S, Dudek-Perić AM, Maes H, et al. 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.
38. Peng SB, Henry JR, Kaufman MD, et al. 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.
39. Zhao X, Wang X, Fang L, et al. A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS-mutant pancreatic cancer. Cancer Lett, 2017, 402: 61-70.
40. Yen I, Shanahan F, Merchant M, et al. Pharmacological induction of RAS-GTP confers RAF inhibitor sensitivity in KRAS mutant tumors. Cancer Cell, 2018, 34(4): 611-625.
41. Bodoky G, Timcheva C, Spigel DR, et al. A phase Ⅱ open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244[ARRY-142886] ) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs, 2012, 30(3): 1216-1223.
42. Wang T, Wei J, Wang N, et al. The glucosylceramide synthase inhibitor PDMP sensitizes pancreatic cancer cells to MEK/ERK inhibitor AZD-6244. Biochem Biophys Res Commun, 2015, 456(3): 821-826.
43. Burmi RS, Maginn EN, Gabra H, et al. 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.
44. Kutkowska J, Strzadala L, Rapak A. Sorafenib in combination with betulinic acid synergistically induces cell cycle arrest and inhibits clonogenic activity in pancreatic ductal adenocarcinoma cells. Int J Mol Sci, 2018, 19(10): E3234.
45. Lopez NE, Prendergast C, Lowy AM. Borderline resectable pancreatic cancer: definitions and management. World J Gastroenterol, 2014, 20(31): 10740-10751.

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