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Targeting KRAS in pancreatic cancer: new drugs on the horizon

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Abstract

Kirsten Rat Sarcoma (KRAS) is a master oncogene involved in cellular proliferation and survival and is the most commonly mutated oncogene in all cancers. Activating KRAS mutations are present in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases and are implicated in tumor initiation and progression. Although KRAS is a critical oncogene, and therefore an important therapeutic target, its therapeutic inhibition has been very challenging, and only recently specific mutant KRAS inhibitors have been discovered. In this review, we discuss the activation of KRAS signaling and the role of mutant KRAS in PDAC development. KRAS has long been considered undruggable, and many drug discovery efforts which focused on indirect targeting have been unsuccessful. We discuss the various efforts for therapeutic targeting of KRAS. Further, we explore the reasons behind these obstacles, novel successful approaches to target mutant KRAS including G12C mutation as well as the mechanisms of resistance.

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References

  1. da Costa, W. L., Jr., A. O. Oluyomi, & Thrift, A. P. (2020). Trends in the incidence of pancreatic adenocarcinoma in all 50 United States examined through an age-period-cohort analysis. JNCI Cancer Spectr, 4(4), pkaa033.

  2. McGuigan, A., et al. (2018). Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World Journal of Gastroenterology, 24(43), 4846–4861.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Siegel, R. L., et al. (2021). Cancer statistics, 2021. CA: A Cancer Journal for Clinicians, 71(1), 7–33.

    Google Scholar 

  4. Waddell, N., et al. (2015). Whole genomes redefine the mutational landscape of pancreatic cancer. Nature, 518(7540), 495–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Witkiewicz, A. K., et al. (2015). Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nature Communications, 6, 6744.

    Article  CAS  PubMed  Google Scholar 

  6. Cancer Genome Atlas Research Network. Electronic address, a.a.d.h.e. and N. Cancer Genome Atlas Research (2017) Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell. 32(2): p. 185–203 e13.

  7. Bailey, P., et al. (2016). Genomic analyses identify molecular subtypes of pancreatic cancer. Nature, 531(7592), 47–52.

    Article  CAS  PubMed  Google Scholar 

  8. Nagasaka, M., et al. (2020). KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat Rev, 84, 101974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Takashima, A., & Faller, D. V. (2013). Targeting the RAS oncogene. Expert Opinion on Therapeutic Targets, 17(5), 507–531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gysin, S., et al. (2011). Therapeutic strategies for targeting ras proteins. Genes & cancer, 2(3), 359–372.

    Article  CAS  Google Scholar 

  11. Müller, M. P., et al. (2017). Nucleotide based covalent inhibitors of KRas can only be efficient in vivo if they bind reversibly with GTP-like affinity. Science and Reports, 7(1), 3687.

    Article  CAS  Google Scholar 

  12. Tong, L. A., et al. (1991). Crystal structures at 2.2 A resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP. Jo Mol Biol, 217(3), 503–16.

    Article  CAS  Google Scholar 

  13. Ostrem, J. M., et al. (2013). K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503(7477), 548–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Prior, I. A., Lewis, P. D., & Mattos, C. (2012). A comprehensive survey of Ras mutations in cancer. Cancer Research, 72(10), 2457–2467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bos, J. L., Rehmann, H., & Wittinghofer, A. (2007). GEFs and GAPs: Critical elements in the control of small G proteins. Cell, 129(5), 865–877.

    Article  CAS  PubMed  Google Scholar 

  16. Hennig, A., et al. (2015). Ras activation revisited: Role of GEF and GAP systems. Biological Chemistry, 396(8), 831–848.

    Article  CAS  PubMed  Google Scholar 

  17. Mann, K. M., et al. (2016). KRAS-related proteins in pancreatic cancer. Pharmacology & Therapeutics, 168, 29–42.

    Article  CAS  Google Scholar 

  18. Moore, A. R., et al. (2020). RAS-targeted therapies: Is the undruggable drugged? Nature Reviews. Drug Discovery, 19(8), 533–552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Logsdon, C. D., & Lu, W. (2016). The significance of Ras activity in pancreatic cancer initiation. International Journal of Biological Sciences, 12(3), 338–346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lennerz, J. K., & Stenzinger, A. (2015). Allelic ratio of KRAS mutations in pancreatic cancer. The Oncologist, 20(4), e8-9.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Patricelli, M. P., et al. (2016). Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discovery, 6(3), 316–329.

    Article  CAS  PubMed  Google Scholar 

  22. Janes, M. R., et al. (2018). Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell, 172(3), 578-589.e17.

    Article  CAS  PubMed  Google Scholar 

  23. Daniluk, J., et al. (2012). An NF-kappaB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. The Journal of Clinical Investigation, 122(4), 1519–1528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Huang, H., et al. (2014). Oncogenic K-Ras requires activation for enhanced activity. Oncogene, 33(4), 532–535.

    Article  CAS  PubMed  Google Scholar 

  25. Hunter, J. C., et al. (2015). Biochemical and structural analysis of common cancer-associated KRAS mutations. Molecular Cancer Research, 13(9), 1325–1335.

    Article  CAS  PubMed  Google Scholar 

  26. Shao, T., et al. (2014). Recombinant expression of different mutant K-ras gene in pancreatic cancer Bxpc-3 cells and its effects on chemotherapy sensitivity. Sci China Life Sci, 57(10), 1011–1017.

    Article  CAS  PubMed  Google Scholar 

  27. Cayron, C. & Guillermet-Guibert, J. (2021). The type of KRAS mutation drives PI3Kα/γ signalling dependency: Implication for the choice of targeted therapy in pancreatic adenocarcinoma patients. Clinics and Research in Hepatology and Gastroenterology, 45(1), 101473.

  28. Ihle, N. T., et al. (2012). Effect of KRAS oncogene substitutions on protein behavior: Implications for signaling and clinical outcome. Journal of the National Cancer Institute, 104(3), 228–239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bournet, B., et al. (2016). KRAS G12D mutation subtype is a prognostic factor for advanced pancreatic adenocarcinoma. Clin Transl Gastroenterol, 7(3), e157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Qian, Z. R., et al. (2018). Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. JAMA Oncology, 4(3), e173420–e173420.

    Article  PubMed  Google Scholar 

  31. Ogura, T., et al. (2013). Prognostic value of K-ras mutation status and subtypes in endoscopic ultrasound-guided fine-needle aspiration specimens from patients with unresectable pancreatic cancer. Journal of Gastroenterology, 48(5), 640–646.

    Article  CAS  PubMed  Google Scholar 

  32. Dhillon, A. S., et al. (2007). MAP kinase signalling pathways in cancer. Oncogene, 26(22), 3279–3290.

    Article  CAS  PubMed  Google Scholar 

  33. Fruman, D. A., et al. (2017). The PI3K pathway in human disease. Cell, 170(4), 605–635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gentry, L. R., et al. (2014). Ral small GTPase signaling and oncogenesis: More than just 15minutes of fame. Biochimica et Biophysica Acta, 1843(12), 2976–2988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang, S., et al. (2011). Pancreatic cancers require autophagy for tumor growth. Genes & Development, 25(7), 717–729.

    Article  CAS  Google Scholar 

  36. Hobbs, G. A., et al. (2020). Atypical KRAS(G12R) mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discovery, 10(1), 104–123.

    Article  CAS  PubMed  Google Scholar 

  37. Suzuki, T., et al. (2021) Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells. Cancer Gene Ther.

  38. Dey, P., et al. (2020). Oncogenic KRAS-driven metabolic reprogramming in pancreatic cancer cells utilizes cytokines from the tumor microenvironment. Cancer Discovery, 10(4), 608–625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pupo, E., et al. (2019). KRAS-driven metabolic rewiring reveals novel actionable targets in cancer. Frontiers in Oncology, 9, 848.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Dias Carvalho, P., et al. (2018). KRAS oncogenic signaling extends beyond cancer cells to orchestrate the microenvironment. Cancer Research, 78(1), 7–14.

    Article  CAS  PubMed  Google Scholar 

  41. Bryant, K. L., et al. (2014). KRAS: Feeding pancreatic cancer proliferation. Trends in Biochemical Sciences, 39(2), 91–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kanda, M., et al. (2012). Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology, 142(4), 730-733.e9.

    Article  CAS  PubMed  Google Scholar 

  43. Hingorani, S. R., et al. (2003). Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell, 4(6), 437–450.

    Article  CAS  PubMed  Google Scholar 

  44. Hingorani, S. R., et al. (2005). Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell, 7(5), 469–483.

    Article  CAS  PubMed  Google Scholar 

  45. Aguirre, A. J., et al. (2003). Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes & Development, 17(24), 3112–3126.

    Article  CAS  Google Scholar 

  46. Collins, M. A., et al. (2012). Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PLoS One, 7(12), e49707.

  47. Collins, M. A., et al. (2012). Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. The Journal of Clinical Investigation, 122(2), 639–653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ying, H., et al. (2012). Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell, 149(3), 656–670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rhim, A. D., et al. (2014). Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell, 25(6), 735–747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bhattacharjee, S., et al. (2021) Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. J Clin Invest, 131(11).

  51. Iwamoto, C., et al. (2021). Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression. Cancer Letters, 512, 15–27.

    Article  CAS  PubMed  Google Scholar 

  52. Hamarsheh, S. A., et al. (2020). Immune modulatory effects of oncogenic KRAS in cancer. Nature Communications, 11(1), 5439–5439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Thayer, S. P., et al. (2003). Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature, 425(6960), 851–856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tian, H., et al. (2009). Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci U S A, 106(11), 4254–4259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Walter, K., et al. (2010). Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts. Clinical Cancer Research, 16(6), 1781–1789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mathew, E., et al. (2014). Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling. Cell Reports, 9(2), 484–494.

    Article  CAS  PubMed  Google Scholar 

  57. Tape, C. J., et al. (2016). Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell, 165(4), 910–920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pu, N., et al. (2019). Genetic landscape of prognostic value in pancreatic ductal adenocarcinoma microenvironment. Ann Transl Med, 7(22), 645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gorchs, L. and H. Kaipe (2021) Interactions between cancer-associated fibroblasts and T cells in the pancreatic tumor microenvironment and the role of chemokines. Cancers (Basel). 13(12).

  60. Ischenko, I., et al. (2021). KRAS drives immune evasion in a genetic model of pancreatic cancer. Nature Communications, 12(1), 1482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Canon, J., et al. (2019). The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature, 575(7781), 217–223.

    Article  CAS  PubMed  Google Scholar 

  62. Briere, D. M., et al. (2021). The KRAS(G12C) inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy. Molecular Cancer Therapeutics, 20(6), 975–985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kato, K., et al. (1992). Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci U S A, 89(14), 6403–6407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ahearn, I. M., et al. (2012). Regulating the regulator: Post-translational modification of RAS. Nature Reviews Molecular Cell Biology, 13(1), 39–51.

    Article  CAS  Google Scholar 

  65. Berndt, N., Hamilton, A. D., & Sebti, S. M. (2011). Targeting protein prenylation for cancer therapy. Nature Reviews Cancer, 11(11), 775–791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wang, W.-h., et al. (2020) Post-translational modification of KRAS: potential targets for cancer therapy. Acta Pharmacologica Sinica.

  67. Brock, E. J., et al. (2016). How to target activated Ras proteins: Direct inhibition vs. induced mislocalization. Mini Rev Med Chem, 16(5), 358–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Brunner, T. B., et al. (2003). Farnesyltransferase inhibitors: An overview of the results of preclinical and clinical investigations. Cancer Research, 63(18), 5656–5668.

    CAS  PubMed  Google Scholar 

  69. Rao, S., et al. (2004). Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. Journal of Clinical Oncology, 22(19), 3950–3957.

    Article  CAS  PubMed  Google Scholar 

  70. Van Cutsem, E., et al. (2004). Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. Journal of Clinical Oncology, 22(8), 1430–1438.

    Article  PubMed  CAS  Google Scholar 

  71. Whyte, D. B., et al. (1997). K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. Journal of Biological Chemistry, 272(22), 14459–14464.

    Article  CAS  PubMed  Google Scholar 

  72. Basso, A. D., Kirschmeier, P., & Bishop, W. R. (2006). Lipid posttranslational modifications Farnesyl transferase inhibitors. J Lipid Res, 47(1), 15–31.

    Article  CAS  PubMed  Google Scholar 

  73. Rowell, C. A., et al. (1997). Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. Journal of Biological Chemistry, 272(22), 14093–14097.

    Article  CAS  PubMed  Google Scholar 

  74. Kazi, A., et al. (2019). Dual farnesyl and geranylgeranyl transferase inhibitor thwarts mutant KRAS-driven patient-derived pancreatic tumors. Clinical Cancer Research, 25(19), 5984–5996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Drosten, M., & Barbacid, M. (2020). Targeting the MAPK pathway in KRAS-driven tumors. Cancer Cell, 37(4), 543–550.

    Article  CAS  PubMed  Google Scholar 

  76. Terrell, E.M. and D.K. Morrison (2019) Ras-mediated activation of the Raf family kinases. Cold Spring Harb Perspect Med, 9(1).

  77. Poulikakos, P. I., et al. (2010). RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature, 464(7287), 427–430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hatzivassiliou, G., et al. (2010). RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature, 464(7287), 431–435.

    Article  CAS  PubMed  Google Scholar 

  79. Heidorn, S. J., et al. (2010). Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell, 140(2), 209–221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sanchez-Laorden, B., et al. (2014) BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. Sci Signal, 7(318): p. ra30.

  81. Peng, S.-B., et al. (2015). Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell, 28(3), 384–398.

    Article  CAS  PubMed  Google Scholar 

  82. Hoxhaj, G., & Manning, B. D. (2020). The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nature Reviews Cancer, 20(2), 74–88.

    Article  CAS  PubMed  Google Scholar 

  83. Missiaglia, E., et al. (2010). Pancreatic endocrine tumors: Expression profiling evidences a role for AKT-mTOR pathway. Journal of Clinical Oncology, 28(2), 245–255.

    Article  CAS  PubMed  Google Scholar 

  84. Yao, J. C., et al. (2011). Everolimus for advanced pancreatic neuroendocrine tumors. New England Journal of Medicine, 364(6), 514–523.

    Article  CAS  PubMed  Google Scholar 

  85. Wolpin, B. M., et al. (2009). Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. Journal of clinical oncology : Official journal of the American Society of Clinical Oncology, 27(2), 193–198.

    Article  CAS  Google Scholar 

  86. Javle, M. M., et al. (2010). Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: Results of two phase II studies. BMC Cancer, 10, 368.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Halilovic, E., et al. (2010). PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling. Cancer Research, 70(17), 6804–6814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Williams, T. M., et al. (2012). Cotargeting MAPK and PI3K signaling with concurrent radiotherapy as a strategy for the treatment of pancreatic cancer. Molecular cancer therapeutics, 11(5), 1193–1202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fell, J. B., et al. (2020). Identification of the clinical development candidate MRTX849, a covalent KRAS(G12C) inhibitor for the treatment of cancer. Journal of Medicinal Chemistry, 63(13), 6679–6693.

    Article  CAS  PubMed  Google Scholar 

  90. Ostrem, J. M., & Shokat, K. M. (2016). Direct small-molecule inhibitors of KRAS: From structural insights to mechanism-based design. Nature Reviews. Drug Discovery, 15(11), 771–785.

    Article  CAS  PubMed  Google Scholar 

  91. Lito, P., et al. (2016). Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science, 351(6273), 604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jackson, P. A., et al. (2017). Covalent modifiers: A chemical perspective on the reactivity of α, β-unsaturated carbonyls with thiols via hetero-Michael addition reactions. Journal of Medicinal Chemistry, 60(3), 839–885.

    Article  CAS  PubMed  Google Scholar 

  93. FDA approves first KRAS inhibitor: Sotorasib. Cancer Discov, 2021.

  94. Skoulidis, F., et al. (2021) Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med.

  95. Hallin, J., et al. (2020). The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer discovery, 10(1), 54–71.

    Article  CAS  PubMed  Google Scholar 

  96. Dogan, S., et al. (2012). Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: Higher susceptibility of women to smoking-related KRAS-mutant cancers. Clinical Cancer Research, 18(22), 6169–6177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhang, Z., et al. (2020). GTP-state-selective cyclic peptide ligands of K-Ras(G12D) block its interaction with Raf. ACS Central Science, 6(10), 1753–1761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dougherty, P. G., Sahni, A., & Pei, D. (2019). Understanding cell penetration of cyclic peptides. Chemical Reviews, 119(17), 10241–10287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sakamoto, K., Masutani, T., & Hirokawa, T. (2020). Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo. Scientific reports, 10(1), 21671–21671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. https://www.mirati.com/science/programs/kras-inhibitors/kras-g12d-inhibitor/ in Mirati Therapeutics Website. Accessed 7 Aug 2021.

  101. Tanaka, N., et al. (2021) Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov.

  102. Liceras-Boillos, P., et al. (2016). Sos1 disruption impairs cellular proliferation and viability through an increase in mitochondrial oxidative stress in primary MEFs. Oncogene, 35(50), 6389–6402.

    Article  CAS  PubMed  Google Scholar 

  103. Hillig, R. C., et al. (2019). Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci U S A, 116(7), 2551–2560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Burns, M. C., et al. (2014). Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proceedings of the National Academy of Sciences, 111(9), 3401.

    Article  CAS  Google Scholar 

  105. Hofmann, M. H., et al. (2021). BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discovery, 11(1), 142–157.

    Article  CAS  PubMed  Google Scholar 

  106. Li, W., et al. (1994). A new function for a phosphotyrosine phosphatase: Linking GRB2-Sos to a receptor tyrosine kinase. Molecular and Cellular Biology, 14(1), 509–517.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Vogel, W., & Ullrich, A. (1996). Multiple in vivo phosphorylated tyrosine phosphatase SHP-2 engages binding to Grb2 via tyrosine 584. Cell Growth & Differentiation, 7(12), 1589–1597.

    CAS  Google Scholar 

  108. Dance, M., et al. (2008). The molecular functions of Shp2 in the Ras/mitogen-activated protein kinase (ERK1/2) pathway. Cellular Signalling, 20(3), 453–459.

    Article  CAS  PubMed  Google Scholar 

  109. Ruess, D. A., et al. (2018). Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nature Medicine, 24(7), 954–960.

    Article  CAS  PubMed  Google Scholar 

  110. Wang, Y., et al. (2021). Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth. EMBO Molecular Medicine, p. e14089.

  111. Heppner, D.E. and M.J. Eck (2021) A structural perspective on targeting the RTK/Ras/MAP kinase pathway in cancer. Protein Sci.

  112. Chen, Y. N., et al. (2016). Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature, 535(7610), 148–152.

    Article  CAS  PubMed  Google Scholar 

  113. Kerr, D. L., Haderk, F., & Bivona, T. G. (2021). Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment. Current Opinion in Chemical Biology, 62, 1–12.

    Article  CAS  PubMed  Google Scholar 

  114. Nichols, R. J., et al. (2018). RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nature Cell Biology, 20(9), 1064–1073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. LaMarche, M. J., et al. (2020). Identification of TNO155, an allosteric SHP2 inhibitor for the treatment of cancer. Journal of Medicinal Chemistry, 63(22), 13578–13594.

    Article  CAS  PubMed  Google Scholar 

  116. Liu, C., et al. (2021). Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clinical Cancer Research, 27(1), 342–354.

    Article  CAS  PubMed  Google Scholar 

  117. Carreno, B. M., et al. (2015). Cancer immunotherapy A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science, 348(6236), 803–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ott, P. A., et al. (2017). An immunogenic personal neoantigen vaccine for patients with melanoma. Nature, 547(7662), 217–221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cafri, G., et al. (2020). mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. The Journal of Clinical Investigation, 130(11), 5976–5988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sahin, U., et al. (2017). Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature, 547(7662), 222–226.

    Article  CAS  PubMed  Google Scholar 

  121. Wang, Z., & Cao, Y. J. (2020). Adoptive cell therapy targeting neoantigens: A frontier for cancer research. Frontiers in Immunology, 11, 176.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Roudko, V., Greenbaum, B., & Bhardwaj, N. (2020). Computational prediction and validation of tumor-associated neoantigens. Frontiers in Immunology, 11, 27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Schumacher, T. N., Scheper, W., & Kvistborg, P. (2018). Cancer neoantigens. Annual Review of Immunology, 37(1), 173–200.

    Article  PubMed  CAS  Google Scholar 

  124. Tran, E., et al. (2016). T-cell transfer therapy targeting mutant KRAS in cancer. New England Journal of Medicine, 375(23), 2255–2262.

    Article  CAS  PubMed  Google Scholar 

  125. Chamberlain, P. P., & Hamann, L. G. (2019). Development of targeted protein degradation therapeutics. Nature Chemical Biology, 15(10), 937–944.

    Article  CAS  PubMed  Google Scholar 

  126. Bond, M. J., et al. (2020). Targeted degradation of oncogenic KRAS(G12C) by VHL-recruiting PROTACs. ACS Central Science, 6(8), 1367–1375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Chandra, A., et al. (2011). The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins. Nature Cell Biology, 14(2), 148–158.

    Article  PubMed  CAS  Google Scholar 

  128. Cheng, J., et al. (2020). Discovery of novel PDEδ degraders for the treatment of KRAS mutant colorectal cancer. Journal of Medicinal Chemistry, 63(14), 7892–7905.

    Article  CAS  PubMed  Google Scholar 

  129. Khan, I., Spencer-Smith, R., & O’Bryan, J. P. (2019). Targeting the α4-α5 dimerization interface of K-RAS inhibits tumor formation in vivo. Oncogene, 38(16), 2984–2993.

    Article  CAS  PubMed  Google Scholar 

  130. Spencer-Smith, R., et al. (2019). Targeting the α4-α5 interface of RAS results in multiple levels of inhibition. Small GTPases, 10(5), 378–387.

    Article  CAS  PubMed  Google Scholar 

  131. Spencer-Smith, R., et al. (2017). Inhibition of RAS function through targeting an allosteric regulatory site. Nature Chemical Biology, 13(1), 62–68.

    Article  CAS  PubMed  Google Scholar 

  132. Khan, I., et al. (2021). Targeting the KRAS α4-α5 allosteric interface inhibits pancreatic cancer tumorigenesis. Small GTPases, p. 1–14.

  133. Jones, S., et al. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 321(5897), 1801–1806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ardito, C. M., et al. (2012). EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell, 22(3), 304–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Navas, C., et al. (2012). EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell, 22(3), 318–330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ryan, M. B., et al. (2020). Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) inhibition. Clinical Cancer Research, 26(7), 1633–1643.

    Article  CAS  PubMed  Google Scholar 

  137. Ahmed, T. A., et al. (2019). SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-Dependent Tumors. Cell Reports, 26(1), 65-78.e5.

    Article  CAS  PubMed  Google Scholar 

  138. Fedele, C., et al. (2018). SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models. Cancer Discovery, 8(10), 1237–1249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Schizas, D., et al. (2020). Immunotherapy for pancreatic cancer: A 2020 update. Cancer Treat Rev, 86, 102016.

    Article  CAS  PubMed  Google Scholar 

  140. Dual RAF-MEK Inhibitor Assessed (2021) Cancer Discov. 11(1): p. 5-6.

  141. Guo, C., et al. (2020). Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: A single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. The lancet Oncology, 21(11), 1478–1488.

    Article  CAS  PubMed  Google Scholar 

  142. Guo, C. and U. Banerji (2021) Searching for treatments for non-G12C-KRAS mutant cancers. Br J Cancer.

  143. Ishii, N., et al. (2013). Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Research, 73(13), 4050–4060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Wada, M., et al. (2014). The dual RAF/MEK inhibitor CH5126766/RO5126766 may be a potential therapy for RAS-mutated tumor cells. PLoS One, 9(11), e113217.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Pachter, RAS targeted drug development meeting 2020. Verastem Oncology Website: https://www.verastem.com/research/raf-mek-inhibition/vs-6766/. Accessed 28 June 2021.

  146. Verastem Oncology Receives Breakthrough Therapy Designation for VS-6766 with Defactinib in Recurrent Low-Grade Serous Ovarian Cancer. Verastem Oncology Press Release. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-receives-breakthrough-therapy-designation-vs. Accessed 28 June 2021.

  147. Sui, X., et al. (2013). Autophagy and chemotherapy resistance: A promising therapeutic target for cancer treatment. Cell Death Dis, 4(10), e838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Wolpin, B. M., et al. (2014). Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. The Oncologist, 19(6), 637–638.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Karasic, T. B., et al. (2019). Effect of gemcitabine and nab-paclitaxel with or without hydroxychloroquine on patients with advanced pancreatic cancer: A phase 2 randomized clinical trial. JAMA Oncology, 5(7), 993–998.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Samaras, P., et al. (2017). Phase I study of a chloroquine-gemcitabine combination in patients with metastatic or unresectable pancreatic cancer. Cancer Chemotherapy and Pharmacology, 80(5), 1005–1012.

    Article  CAS  PubMed  Google Scholar 

  151. Awad, M. M., et al. (2021). Acquired resistance to KRAS(G12C) inhibition in cancer. New England Journal of Medicine, 384(25), 2382–2393.

    Article  CAS  PubMed  Google Scholar 

  152. Brown, W. S., et al. (2020). Overcoming adaptive resistance to KRAS and MEK inhibitors by co-targeting mTORC1/2 complexes in pancreatic cancer. Cell Rep Med, 1(8), 100131.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Schmidt, K. M., et al. (2017). Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models. Oncotarget, 8(15), 24491–24505.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Driscoll, D. R., et al. (2016). mTORC2 signaling drives the development and progression of pancreatic cancer. Cancer Research, 76(23), 6911–6923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Soares, H. P., et al. (2015). Dual PI3K/mTOR inhibitors induce rapid overactivation of the MEK/ERK pathway in human pancreatic cancer cells through suppression of mTORC2. Molecular Cancer Therapeutics, 14(4), 1014–1023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Chen, P. Y., et al. (2018). Adaptive and reversible resistance to kras inhibition in pancreatic cancer cells. Cancer Research, 78(4), 985–1002.

    Article  CAS  PubMed  Google Scholar 

  157. Ryan, D. P., Hong, T. S., & Bardeesy, N. (2014). Pancreatic adenocarcinoma. New England Journal of Medicine, 371(11), 1039–1049.

    Article  CAS  PubMed  Google Scholar 

  158. Cirri, P., & Chiarugi, P. (2012). Cancer-associated-fibroblasts and tumour cells: A diabolic liaison driving cancer progression. Cancer and Metastasis Reviews, 31(1–2), 195–208.

    Article  PubMed  Google Scholar 

  159. Kerk, S.A., et al. (2021) Metabolic networks in mutant KRAS-driven tumours: Tissue specificities and the microenvironment. Nat Rev Cancer.

  160. Sherman, M. H., et al. (2014). Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell, 159(1), 80–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Hou, P., et al. (2020). Tumor microenvironment remodeling enables bypass of oncogenic KRAS dependency in pancreatic cancer. Cancer Discovery, 10(7), 1058–1077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Chaudhri, V. K., et al. (2013). Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Molecular Cancer Research, 11(6), 579–592.

    Article  CAS  PubMed  Google Scholar 

  163. Sousa, C. M., et al. (2016). Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature, 536(7617), 479–483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhao, H., et al. (2016). Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife, 5, e10250.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Dalin, S., et al. (2019). Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance. Cancer Research, 79(22), 5723–5733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Halbrook, C.J., et al. (2019) Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metab, 29(6): 1390–1399 e6.

  167. Yan, Y., et al. (2019). The effects and the mechanisms of autophagy on the cancer-associated fibroblasts in cancer. Journal of Experimental & Clinical Cancer Research, 38(1), 171.

    Article  Google Scholar 

  168. Banh, R.S., et al. (2020) Neurons release serine to support mRNA translation in pancreatic cancer. Cell, 183(5): 1202–1218 e25.

  169. Pei, Y., et al. (2019) Sequential targeting TGF-beta signaling and KRAS mutation increases therapeutic efficacy in Pancreatic Cancer. Small, 15(24): p. e1900631.

  170. Fedele, C. et al. (2021) SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med, 218(1).

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Funding

Work in the lab of Azmi AS is supported by R37CA215427, R01CA24060701A1, and SKY Foundation Inc.

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Authors and Affiliations

  1. Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Sahar F. Bannoura, Md. Hafiz Uddin, Farzeen Fazili, Mohammed Najeeb Al-Hallak, Philip A. Philip & Asfar S. Azmi

  2. Division of Hematology/Oncology, Department of Medicine, UCI Health, Orange, CA, 92868, USA

    Misako Nagasaka

  3. Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA

    Bassel El-Rayes

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  1. Sahar F. Bannoura
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  2. Md. Hafiz Uddin
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  5. Mohammed Najeeb Al-Hallak
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  8. Asfar S. Azmi
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Correspondence to Asfar S. Azmi.

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ASA received funding from Karyopharm Therapeutics, Janssen, Rhizen, and EISAI. ASA serves as a consultant for GLG and Guidepoint.

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Bannoura, S.F., Uddin, M.H., Nagasaka, M. et al. Targeting KRAS in pancreatic cancer: new drugs on the horizon. Cancer Metastasis Rev 40, 819–835 (2021). https://doi.org/10.1007/s10555-021-09990-2

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