1932

Abstract

Here we discuss approaches to K-Ras inhibition and drug resistance scenarios. A breakthrough offered a covalent drug against K-RasG12C. Subsequent innovations harnessed same-allele drug combinations, as well as cotargeting K-RasG12C with a companion drug to upstream regulators or downstream kinases. However, primary, adaptive, and acquired resistance inevitably emerge. The preexisting mutation load can explain how even exceedingly rare mutations with unobservable effects can promote drug resistance, seeding growth of insensitive cell clones, and proliferation. Statistics confirm the expectation that most resistance-related mutations are in , pointing to the high probability of cooperative, same-allele effects. In addition to targeted Ras inhibitors and drug combinations, bifunctional molecules and innovative tri-complex inhibitors to target Ras mutants are also under development. Since the identities and potential contributions of preexisting and evolving mutations are unknown, selecting a pharmacologic combination is taxing. Collectively, our broad review outlines considerations and provides new insights into pharmacology and resistance.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-022823-113946
2024-01-23
2024-10-06
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/64/1/annurev-pharmtox-022823-113946.html?itemId=/content/journals/10.1146/annurev-pharmtox-022823-113946&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Nussinov R, Jang H, Gursoy A, Keskin O, Gaponenko V. 2021. Inhibition of nonfunctional Ras. Cell Chem. Biol. 28:121–33
    [Google Scholar]
  2. 2.
    Punekar SR, Velcheti V, Neel BG, Wong KK. 2022. The current state of the art and future trends in RAS-targeted cancer therapies. Nat. Rev. Clin. Oncol. 19:637–55
    [Google Scholar]
  3. 3.
    Zhao Y, Murciano-Goroff YR, Xue JY, Ang A, Lucas J et al. 2021. Diverse alterations associated with resistance to KRASG12C inhibition. Nature 599:679–83
    [Google Scholar]
  4. 4.
    Lietman CD, Johnson ML, McCormick F, Lindsay CR. 2022. More to the RAS story: KRASG12C inhibition, resistance mechanisms, and moving beyond KRASG12C. Am. Soc. Clin. Oncol. Educ. Book 42:1–13
    [Google Scholar]
  5. 5.
    Shetu SA, Bandyopadhyay D. 2022. Small-molecule RAS inhibitors as anticancer agents: discovery, development, and mechanistic studies. Int. J. Mol. Sci. 23:3706
    [Google Scholar]
  6. 6.
    Hobbs GA, Der CJ, Rossman KL. 2016. RAS isoforms and mutations in cancer at a glance. J. Cell Sci. 129:1287–92
    [Google Scholar]
  7. 7.
    Simanshu DK, Nissley DV, McCormick F. 2017. RAS proteins and their regulators in human disease. Cell 170:17–33
    [Google Scholar]
  8. 8.
    Nassar AH, Adib E, Kwiatkowski DJ. 2021. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N. Engl. J. Med. 384:185–87
    [Google Scholar]
  9. 9.
    Prior IA, Hood FE, Hartley JL. 2020. The frequency of Ras mutations in cancer. Cancer Res. 80:2969–74
    [Google Scholar]
  10. 10.
    AACR Proj. GENIE Consort 2017. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov. 7:818–31
    [Google Scholar]
  11. 11.
    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO et al. 2012. The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–4
    [Google Scholar]
  12. 12.
    Zehir A, Benayed R, Shah RH, Syed A, Middha S et al. 2017. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23:703–13
    [Google Scholar]
  13. 13.
    Skoulidis F, Heymach JV. 2019. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat. Rev. Cancer 19:495–509
    [Google Scholar]
  14. 14.
    Cancer Genome Atlas Res. Netw 2014. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543–50
    [Google Scholar]
  15. 15.
    Jordan EJ, Kim HR, Arcila ME, Barron D, Chakravarty D et al. 2017. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7:596–609
    [Google Scholar]
  16. 16.
    Zhang J, Zhang J, Liu Q, Fan X-X, Leung EL et al. 2022. Resistance looms for KRAS G12C inhibitors and rational tackling strategies. Pharmacol. Ther. 229:108050
    [Google Scholar]
  17. 17.
    Sun R, Hou Z, Zhang Y, Jiang B. 2022. Drug resistance mechanisms and progress in the treatment of EGFR-mutated lung adenocarcinoma. Oncol. Lett. 24:408
    [Google Scholar]
  18. 18.
    East P, Kelly GP, Biswas D, Marani M, Hancock DC et al. 2022. RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma. Nat. Commun. 13:5632
    [Google Scholar]
  19. 19.
    Warren HR, Ross SJ, Smith PD, Coulson JM, Prior IA. 2022. Combinatorial approaches for mitigating resistance to KRAS-targeted therapies. Biochem. J. 479:1985–97
    [Google Scholar]
  20. 20.
    Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J et al. 2021. Acquired resistance to KRASG12C inhibition in cancer. N. Engl. J. Med. 384:2382–93
    [Google Scholar]
  21. 21.
    Zhang Y, Xia M, Jin K, Wang S, Wei H et al. 2018. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol. Cancer 17:45
    [Google Scholar]
  22. 22.
    Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J 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. 11:1913–22
    [Google Scholar]
  23. 23.
    Nussinov R, Tsai CJ, Jang H. 2021. Anticancer drug resistance: an update and perspective. Drug Resist. Updat. 59:100796
    [Google Scholar]
  24. 24.
    Nussinov R, Tsai CJ. 2015.. ‘ Latent drivers’ expand the cancer mutational landscape. Curr. Opin. Struct. Biol. 32:25–32
    [Google Scholar]
  25. 25.
    Zhao Y, Xue JY, Lito P. 2021. Suppressing nucleotide exchange to inhibit KRAS-mutant tumors. Cancer Discov. 11:17–19
    [Google Scholar]
  26. 26.
    Gimple RC, Wang X. 2019. RAS: striking at the core of the oncogenic circuitry. Front. Oncol. 9:965
    [Google Scholar]
  27. 27.
    Hymowitz SG, Malek S. 2018. Targeting the MAPK pathway in RAS mutant cancers. Cold Spring Harb. Perspect. Med. 8:a031492
    [Google Scholar]
  28. 28.
    Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA et al. 2020. KRASG12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383:1207–17
    [Google Scholar]
  29. 29.
    Sattler M, Mohanty A, Kulkarni P, Salgia R. 2023. Precision oncology provides opportunities for targeting KRAS-inhibitor resistance. Trends Cancer 9:42–54
    [Google Scholar]
  30. 30.
    Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. 2017. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168:707–23
    [Google Scholar]
  31. 31.
    Bandaru P, Kondo Y, Kuriyan J. 2019. The interdependent activation of Son-of-Sevenless and Ras. Cold Spring Harb. Perspect. Med. 9:a031534
    [Google Scholar]
  32. 32.
    Huang WYC, Alvarez S, Kondo Y, Lee YK, Chung JK et al. 2019. A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS. Science 363:1098–103
    [Google Scholar]
  33. 33.
    Liao J, Shima F, Araki M, Ye M, Muraoka S et al. 2008. Two conformational states of Ras GTPase exhibit differential GTP-binding kinetics. Biochem. Biophys. Res. Commun. 369:327–32
    [Google Scholar]
  34. 34.
    Nussinov R, Tsai CJ, Jang H. 2019. Is nanoclustering essential for all oncogenic KRas pathways? Can it explain why wild-type KRas can inhibit its oncogenic variant?. Semin. Cancer Biol. 54:114–20
    [Google Scholar]
  35. 35.
    Šolman M, Ligabue A, Blazevits O, Jaiswal A, Zhou Y et al. 2015. Specific cancer-associated mutations in the switch III region of Ras increase tumorigenicity by nanocluster augmentation. eLife 4:e08905
    [Google Scholar]
  36. 36.
    Sutton MN, Lu Z, Li YC, Zhou Y, Huang T et al. 2019. DIRAS3 (ARHI) blocks RAS/MAPK signaling by binding directly to RAS and disrupting RAS clusters. Cell Rep. 29:3448–59.e6
    [Google Scholar]
  37. 37.
    Lavoie H, Thevakumaran N, Gavory G, Li JJ, Padeganeh A et al. 2013. Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization. Nat. Chem. Biol. 9:428–36
    [Google Scholar]
  38. 38.
    Lee Y, Phelps C, Huang T, Mostofian B, Wu L et al. 2019. High-throughput, single-particle tracking reveals nested membrane domains that dictate KRasG12D diffusion and trafficking. eLife 8:e46393
    [Google Scholar]
  39. 39.
    Fang Z, Lee KY, Huo KG, Gasmi-Seabrook G, Zheng L et al. 2020. Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane. PNAS 117:12101–8
    [Google Scholar]
  40. 40.
    Travers T, Lopez CA, Van QN, Neale C, Tonelli M et al. 2018. Molecular recognition of RAS/RAF complex at the membrane: role of RAF cysteine-rich domain. Sci. Rep. 8:8461
    [Google Scholar]
  41. 41.
    Kondo Y, Ognjenovic J, Banerjee S, Karandur D, Merk A et al. 2019. Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases. Science 366:109–15
    [Google Scholar]
  42. 42.
    Park E, Rawson S, Li K, Kim BW, Ficarro SB et al. 2019. Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. Nature 575:545–50
    [Google Scholar]
  43. 43.
    Zhang M, Jang H, Li Z, Sacks DB, Nussinov R. 2021. B-Raf autoinhibition in the presence and absence of 14-3-3. Structure 29:768–77.e2
    [Google Scholar]
  44. 44.
    Rezaei Adariani S, Buchholzer M, Akbarzadeh M, Nakhaei-Rad S, Dvorsky R, Ahmadian MR 2018. Structural snapshots of RAF kinase interactions. Biochem. Soc. Trans. 46:1393–406
    [Google Scholar]
  45. 45.
    De Luca A, Maiello MR, D'Alessio A, Pergameno M, Normanno N 2012. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin. Ther. Targets 16:Suppl. 2S17–27
    [Google Scholar]
  46. 46.
    Maloney RC, Zhang M, Liu Y, Jang H, Nussinov R. 2022. The mechanism of activation of MEK1 by B-Raf and KSR1. Cell Mol. Life Sci. 79:281
    [Google Scholar]
  47. 47.
    Gul A, Leyland-Jones B, Dey N, De P. 2018. A combination of the PI3K pathway inhibitor plus cell cycle pathway inhibitor to combat endocrine resistance in hormone receptor-positive breast cancer: a genomic algorithm-based treatment approach. Am. J. Cancer Res. 8:2359–76
    [Google Scholar]
  48. 48.
    Lien EC, Dibble CC, Toker A. 2017. PI3K signaling in cancer: beyond AKT. Curr. Opin. Cell Biol. 45:62–71
    [Google Scholar]
  49. 49.
    Pokrass MJ, Ryan KA, Xin T, Pielstick B, Timp W et al. 2020. Cell-cycle-dependent ERK signaling dynamics direct fate specification in the mammalian preimplantation embryo. Dev. Cell 55:328–40.e5
    [Google Scholar]
  50. 50.
    Zhang M, Jang H, Nussinov R. 2020. PI3K inhibitors: review and new strategies. Chem. Sci. 11:5855–65
    [Google Scholar]
  51. 51.
    Lavoie H, Gagnon J, Therrien M. 2020. ERK signalling: a master regulator of cell behaviour, life and fate. Nat. Rev. Mol. Cell Biol. 21:607–32
    [Google Scholar]
  52. 52.
    Zhang M, Jang H, Nussinov R. 2019. The mechanism of PI3Kα activation at the atomic level. Chem. Sci. 10:3671–80
    [Google Scholar]
  53. 53.
    Cargnello M, Tcherkezian J, Roux PP. 2015. The expanding role of mTOR in cancer cell growth and proliferation. Mutagenesis 30:169–76
    [Google Scholar]
  54. 54.
    Ijuin T. 2019. Phosphoinositide phosphatases in cancer cell dynamics—beyond PI3K and PTEN. Semin. Cancer Biol. 59:50–65
    [Google Scholar]
  55. 55.
    Yehia L, Eng C. 2020. PTEN hamartoma tumour syndrome: What happens when there is no PTEN germline mutation?. Hum. Mol. Genet. 29:R150–57
    [Google Scholar]
  56. 56.
    Nussinov R, Tsai CJ, Jang H. 2018. Oncogenic Ras isoforms signaling specificity at the membrane. Cancer Res. 78:593–602
    [Google Scholar]
  57. 57.
    Barklis E, Stephen AG, Staubus AO, Barklis RL, Alfadhli A. 2019. Organization of farnesylated, carboxymethylated KRAS4B on membranes. J. Mol. Biol. 431:3706–17
    [Google Scholar]
  58. 58.
    Ahearn IM, Haigis K, Bar-Sagi D, Philips MR. 2011. Regulating the regulator: post-translational modification of RAS. Nat. Rev. Mol. Cell Biol. 13:39–51
    [Google Scholar]
  59. 59.
    Cao S, Chung S, Kim S, Li Z, Manor D, Buck M. 2019. K-Ras G-domain binding with signaling lipid phosphatidylinositol (4,5)-phosphate (PIP2): membrane association, protein orientation, and function. J. Biol. Chem. 294:7068–84
    [Google Scholar]
  60. 60.
    Prakash P, Litwin D, Liang H, Sarkar-Banerjee S, Dolino D et al. 2019. Dynamics of membrane-bound G12V-KRAS from simulations and single-molecule FRET in native nanodiscs. Biophys. J. 116:179–83
    [Google Scholar]
  61. 61.
    Baietti MF, Simicek M, Abbasi Asbagh L, Radaelli E, Lievens S et al. 2016. OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination. EMBO Mol. Med. 8:288–303
    [Google Scholar]
  62. 62.
    Steklov M, Pandolfi S, Baietti MF, Batiuk A, Carai P et al. 2018. Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. Science 362:1177–82
    [Google Scholar]
  63. 63.
    Thurman R, Siraliev-Perez E, Campbell SL. 2020. RAS ubiquitylation modulates effector interactions. Small GTPases 11:180–85
    [Google Scholar]
  64. 64.
    Lamontanara AJ, Georgeon S, Tria G, Svergun DI, Hantschel O. 2014. The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility. Nat. Commun. 5:5470
    [Google Scholar]
  65. 65.
    Vetter IR, Wittinghofer A. 2001. The guanine nucleotide-binding switch in three dimensions. Science 294:1299–304
    [Google Scholar]
  66. 66.
    Wittinghofer A, Vetter IR. 2011. Structure-function relationships of the G domain, a canonical switch motif. Annu. Rev. Biochem. 80:943–71
    [Google Scholar]
  67. 67.
    Smith MJ, Ikura M. 2014. Integrated RAS signaling defined by parallel NMR detection of effectors and regulators. Nat. Chem. Biol. 10:223–30
    [Google Scholar]
  68. 68.
    Vigil D, Cherfils J, Rossman KL, Der CJ. 2010. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?. Nat. Rev. Cancer 10:842–57
    [Google Scholar]
  69. 69.
    Nussinov R, Jang H, Tsai CJ. 2014. The structural basis for cancer treatment decisions. Oncotarget 5:7285–302
    [Google Scholar]
  70. 70.
    Martin-Garcia F, Mendieta-Moreno JI, Lopez-Vinas E, Gomez-Puertas P, Mendieta J. 2012. The role of Gln61 in HRas GTP hydrolysis: a quantum mechanics/molecular mechanics study. Biophys. J. 102:152–57
    [Google Scholar]
  71. 71.
    Poulin EJ, Bera AK, Lu J, Lin YJ, Strasser SD et al. 2019. Tissue-specific oncogenic activity of KRASA146T. Cancer Discov. 9:738–55
    [Google Scholar]
  72. 72.
    Parker JA, Volmar AY, Pavlopoulos S, Mattos C. 2018. K-Ras populates conformational states differently from its isoform H-Ras and oncogenic mutant K-RasG12D. Structure 26:810–20e4
    [Google Scholar]
  73. 73.
    Parker JA, Mattos C. 2018. The K-Ras, N-Ras, and H-Ras isoforms: unique conformational preferences and implications for targeting oncogenic mutants. Cold Spring Harb. Perspect. Med. 8:a031427
    [Google Scholar]
  74. 74.
    Zhang Z, Guiley KZ, Shokat KM. 2022. Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S). Nat. Chem. Biol. 18:1177–83
    [Google Scholar]
  75. 75.
    Hobbs GA, Baker NM, Miermont AM, Thurman RD, Pierobon M et al. 2020. Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discov. 10:104–23
    [Google Scholar]
  76. 76.
    Grudzien P, Jang H, Leschinsky N, Nussinov R, Gaponenko V. 2022. Conformational dynamics allows sampling of an “active-like” state by oncogenic K-Ras-GDP. J. Mol. Biol. 434:167695
    [Google Scholar]
  77. 77.
    Akdemir KC, Le VT, Kim JM, Killcoyne S, King DA et al. 2020. Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure. Nat. Genet. 52:1178–88
    [Google Scholar]
  78. 78.
    Martincorena I, Campbell PJ. 2015. Somatic mutation in cancer and normal cells. Science 349:1483–89
    [Google Scholar]
  79. 79.
    Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM et al. 2019. COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 47:D941–47
    [Google Scholar]
  80. 80.
    Pon JR, Marra MA. 2015. Driver and passenger mutations in cancer. Annu. Rev. Pathol. Mech. Dis. 10:25–50
    [Google Scholar]
  81. 81.
    Nussinov R, Jang H, Tsai CJ, Cheng F. 2019. Precision medicine and driver mutations: computational methods, functional assays and conformational principles for interpreting cancer drivers. PLOS Comput. Biol. 15:e1006658
    [Google Scholar]
  82. 82.
    Nussinov R, Tsai CJ, Jang H. 2019. Why are some driver mutations rare?. Trends Pharmacol. Sci. 40:919–29
    [Google Scholar]
  83. 83.
    Nussinov R, Jang H, Tsai CJ, Cheng F. 2019. Precision medicine review: rare driver mutations and their biophysical classification. Biophys. Rev. 11:5–19
    [Google Scholar]
  84. 84.
    Beckman RA, Loeb LA. 2020. Rare mutations in cancer drug resistance and implications for therapy. Clin. Pharmacol. Ther. 108:437–39
    [Google Scholar]
  85. 85.
    Loeb LA, Kohrn BF, Loubet-Senear KJ, Dunn YJ, Ahn EH et al. 2019. Extensive subclonal mutational diversity in human colorectal cancer and its significance. PNAS 116:26863–72
    [Google Scholar]
  86. 86.
    Reiter JG, Baretti M, Gerold JM, Makohon-Moore AP, Daud A et al. 2019. An analysis of genetic heterogeneity in untreated cancers. Nat. Rev. Cancer 19:639–50
    [Google Scholar]
  87. 87.
    Gao L, Wu ZX, Assaraf YG, Chen ZS, Wang L. 2021. Overcoming anti-cancer drug resistance via restoration of tumor suppressor gene function. Drug Resist. Updat. 57:100770
    [Google Scholar]
  88. 88.
    Nicolini FE, Ibrahim AR, Soverini S, Martinelli G, Muller MC et al. 2013. The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis. Haematologica 98:1510–16
    [Google Scholar]
  89. 89.
    Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG et al. 2010. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463:501–6
    [Google Scholar]
  90. 90.
    Tamai M, Inukai T, Kojika S, Abe M, Kagami K et al. 2018. T315I mutation of BCR-ABL1 into human Philadelphia chromosome-positive leukemia cell lines by homologous recombination using the CRISPR/Cas9 system. Sci. Rep. 8:9966
    [Google Scholar]
  91. 91.
    Smyth LA, Collins I. 2009. Measuring and interpreting the selectivity of protein kinase inhibitors. J. Chem. Biol. 2:131–51
    [Google Scholar]
  92. 92.
    John J, Sohmen R, Feuerstein J, Linke R, Wittinghofer A, Goody RS. 1990. Kinetics of interaction of nucleotides with nucleotide-free H-ras p21. Biochemistry 29:6058–65
    [Google Scholar]
  93. 93.
    Traut TW. 1994. Physiological concentrations of purines and pyrimidines. Mol. Cell Biochem. 140:1–22
    [Google Scholar]
  94. 94.
    Pinnelli M, Trusolino L. 2021. The gRASs is greener: potential new therapies in lung cancer with acquired resistance to KRASG12C inhibitors. Cancer Discov. 11:1874–76
    [Google Scholar]
  95. 95.
    Bery N, Legg S, Debreczeni J, Breed J, Embrey K et al. 2019. KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe. Nat. Commun. 10:2607
    [Google Scholar]
  96. 96.
    Baranyi M, Buday L, Hegedus B. 2020. K-Ras prenylation as a potential anticancer target. Cancer Metastasis Rev. 39:1127–41
    [Google Scholar]
  97. 97.
    Cheng J, Li Y, Wang X, Dong G, Sheng C. 2020. Discovery of novel PDEδ degraders for the treatment of KRAS mutant colorectal cancer. J. Med. Chem. 63:7892–905
    [Google Scholar]
  98. 98.
    Quevedo CE, Cruz-Migoni A, Bery N, Miller A, Tanaka T et al. 2018. Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment. Nat. Commun. 9:3169
    [Google Scholar]
  99. 99.
    Spencer-Smith R, O'Bryan JP 2019. Direct inhibition of RAS: quest for the holy grail?. Semin. Cancer Biol. 54:138–48
    [Google Scholar]
  100. 100.
    Chatani PD, Yang JC. 2020. Mutated RAS: targeting the “untargetable” with T cells. Clin. Cancer Res. 26:537–44
    [Google Scholar]
  101. 101.
    Gentile DR, Rathinaswamy MK, Jenkins ML, Moss SM, Siempelkamp BD et al. 2017. Ras binder induces a modified switch-II pocket in GTP and GDP states. Cell Chem. Biol. 24:1455–66.e14
    [Google Scholar]
  102. 102.
    Khan I, Rhett JM, O'Bryan JP 2020. Therapeutic targeting of RAS: new hope for drugging the “undruggable. .” Biochim. Biophys. Acta Mol. Cell Res. 1867:118570
    [Google Scholar]
  103. 103.
    Liu P, Wang Y, Li X. 2019. Targeting the untargetable KRAS in cancer therapy. Acta Pharm. Sin. B 9:871–79
    [Google Scholar]
  104. 104.
    Mullard A. 2019. Cracking KRAS. Nat. Rev. Drug Discov. 18:887–91
    [Google Scholar]
  105. 105.
    O'Bryan JP. 2019. Pharmacological targeting of RAS: recent success with direct inhibitors. Pharmacol. Res. 139:503–11
    [Google Scholar]
  106. 106.
    Patricelli MP, Janes MR, Li LS, Hansen R, Peters U et al. 2016. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 6:316–29
    [Google Scholar]
  107. 107.
    Sheridan C. 2020. Grail of RAS cancer drugs within reach. Nat. Biotechnol. 38:6–8
    [Google Scholar]
  108. 108.
    Zhang Z, Shokat KM. 2019. Bifunctional small-molecule ligands of K-Ras induce its association with immunophilin proteins. Angew. Chem. Int. Ed. Engl. 58:16314–19
    [Google Scholar]
  109. 109.
    Xiong Y, Lu J, Hunter J, Li L, Scott D et al. 2017. Covalent guanosine mimetic inhibitors of G12C KRAS. ACS Med. Chem. Lett. 8:61–66
    [Google Scholar]
  110. 110.
    Janes MR, Zhang J, Li LS, Hansen R, Peters U et al. 2018. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172:578–89.e17
    [Google Scholar]
  111. 111.
    Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS et al. 2021. Sotorasib for lung cancers with KRAS p.G12C mutation. N. Engl. J. Med. 384:2371–81
    [Google Scholar]
  112. 112.
    Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R et al. 2020. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10:54–71
    [Google Scholar]
  113. 113.
    Kessler D, Gmachl M, Mantoulidis A, Martin LJ, Zoephel A et al. 2019. Drugging an undruggable pocket on KRAS. PNAS 116:15823–29
    [Google Scholar]
  114. 114.
    Kessler D, Gollner A, Gmachl M, Mantoulidis A, Martin LJ et al. 2020. Reply to Tran et al.: Dimeric KRAS protein-protein interaction stabilizers. PNAS 117:3365–67
    [Google Scholar]
  115. 115.
    Tran TH, Alexander P, Dharmaiah S, Agamasu C, Nissley DV et al. 2020. The small molecule BI-2852 induces a nonfunctional dimer of KRAS. PNAS 117:3363–64
    [Google Scholar]
  116. 116.
    Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. 2013. K-RasG12C inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548–51
    [Google Scholar]
  117. 117.
    Ostrem JM, Shokat KM. 2016. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat. Rev. Drug Discov. 15:771–85
    [Google Scholar]
  118. 118.
    Daneri-Becerra C, Valeiras B, Gallo LI, Lagadari M, Galigniana MD. 2021. Cyclophilin A is a mitochondrial factor that forms complexes with p23—correlative evidence for an anti-apoptotic action. J. Cell Sci. 134:jcs253401
    [Google Scholar]
  119. 119.
    Tsuji K, Hymel D, Ma B, Tamamura H, Nussinov R, Burke TR Jr. 2022. Development of ultra-high affinity bivalent ligands targeting the polo-like kinase 1. RSC Chem. Biol. 3:1111–20
    [Google Scholar]
  120. 120.
    Zhang Z, Morstein J, Ecker AK, Guiley KZ, Shokat KM. 2022. Chemoselective covalent modification of K-Ras(G12R) with a small molecule electrophile. J. Am. Chem. Soc. 144:15916–21
    [Google Scholar]
  121. 121.
    Zheng Q, Peacock DM, Shokat KM. 2022. Drugging the next undruggable KRAS allele—Gly12Asp. J. Med. Chem. 65:3119–22
    [Google Scholar]
  122. 122.
    Feng S, Callow MG, Fortin JP, Khan Z, Bray D et al. 2022. A saturation mutagenesis screen uncovers resistant and sensitizing secondary KRAS mutations to clinical KRASG12C inhibitors. PNAS 119:e2120512119
    [Google Scholar]
  123. 123.
    Hattori T, Maso L, Araki KY, Koide A, Hayman J et al. 2023. Creating MHC-restricted neoantigens with covalent inhibitors that can be targeted by immune therapy. Cancer Discov 13:132–45
    [Google Scholar]
  124. 124.
    Zhang Z, Rohweder PJ, Ongpipattanakul C, Basu K, Bohn MF et al. 2022. A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy. Cancer Cell 40:1060–69.e7
    [Google Scholar]
  125. 125.
    Ryan MB, Corcoran RB. 2018. Therapeutic strategies to target RAS-mutant cancers. Nat. Rev. Clin. Oncol. 15:709–20
    [Google Scholar]
  126. 126.
    Kim TK, Herbst RS, Chen L. 2018. Defining and understanding adaptive resistance in cancer immunotherapy. Trends Immunol. 39:624–31
    [Google Scholar]
  127. 127.
    Assaraf YG, Brozovic A, Goncalves AC, Jurkovicova D, Line A et al. 2019. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist. Updat. 46:100645
    [Google Scholar]
  128. 128.
    Shahar N, Larisch S. 2020. Inhibiting the inhibitors: targeting anti-apoptotic proteins in cancer and therapy resistance. Drug Resist. Updat. 52:100712
    [Google Scholar]
  129. 129.
    Ruess DA, Heynen GJ, Ciecielski KJ, Ai J, Berninger A et al. 2018. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat. Med. 24:954–60
    [Google Scholar]
  130. 130.
    Mainardi S, Mulero-Sanchez A, Prahallad A, Germano G, Bosma A et al. 2018. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat. Med. 24:961–67
    [Google Scholar]
  131. 131.
    Pfeiffer A, Franciosa G, Locard-Paulet M, Piga I, Reckzeh K et al. 2022. Phosphorylation of SHP2 at Tyr62 enables acquired resistance to SHP2 allosteric inhibitors in FLT3-ITD-driven AML. Cancer Res 82:2141–55
    [Google Scholar]
  132. 132.
    Fakih M, Durm GA, Govindan R, Falchook GS, Soman N et al. Trial in progress: a phase Ib study of AMG 510, a specific and irreversible KRASG12C inhibitor, in combination with other anticancer therapies in patients with advanced solid tumors harboring KRAS p.G12C mutation (CodeBreak 101). J. Clin. Oncol. 38:Suppl. 15TPS3661 Abstr. )
    [Google Scholar]
  133. 133.
    Salgia R, Pharaon R, Mambetsariev I, Nam A, Sattler M. 2021. The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC). Cell Rep. Med. 2:100186
    [Google Scholar]
  134. 134.
    Kwan AK, Piazza GA, Keeton AB, Leite CA. 2022. The path to the clinic: a comprehensive review on direct KRASG12C inhibitors. J. Exp. Clin. Cancer Res. 41:27
    [Google Scholar]
  135. 135.
    Hofmann MH, Gerlach D, Misale S, Petronczki M, Kraut N. 2022. Expanding the reach of precision oncology by drugging all KRAS mutants. Cancer Discov. 12:924–37
    [Google Scholar]
  136. 136.
    Nussinov R, Jang H, Nir G, Tsai CJ, Cheng F. 2021. A new precision medicine initiative at the dawn of exascale computing. Signal Transduct. Target. Ther. 6:3
    [Google Scholar]
  137. 137.
    Getzenberg RH, Coffey DS. 2011. Changing the energy habitat of the cancer cell in order to impact therapeutic resistance. Mol. Pharm. 8:2089–93
    [Google Scholar]
  138. 138.
    Nussinov R, Zhang M, Maloney R, Jang H. 2021. Drugging multiple same-allele driver mutations in cancer. Expert Opin. Drug Discov. 16:823–28
    [Google Scholar]
  139. 139.
    Saito Y, Koya J, Araki M, Kogure Y, Shingaki S et al. 2020. Landscape and function of multiple mutations within individual oncogenes. Nature 582:95–99
    [Google Scholar]
  140. 140.
    Vasan N, Razavi P, Johnson JL, Shao H, Shah H et al. 2019. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. Science 366:714–23
    [Google Scholar]
  141. 141.
    Zhang M, Jang H, Nussinov R. 2021. PI3K driver mutations: a biophysical membrane-centric perspective. Cancer Res. 81:237–47
    [Google Scholar]
  142. 142.
    Haupt S, Zeilmann A, Ahadova A, Blaker H, von Knebel Doeberitz M et al. 2021. Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with Kronecker structure. PLOS Comput. Biol. 17:e1008970
    [Google Scholar]
  143. 143.
    Nussinov R, Tsai CJ, Jang H. 2020. Are parallel proliferation pathways redundant?. Trends Biochem. Sci. 45:554–63
    [Google Scholar]
  144. 144.
    Akdemir KC, Le VT, Chandran S, Li Y, Verhaak RG et al. 2020. Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer. Nat. Genet. 52:294–305
    [Google Scholar]
  145. 145.
    Madsen RR, Knox RG, Pearce W, Lopez S, Mahler-Araujo B et al. 2019. Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner. PNAS 116:8380–89
    [Google Scholar]
  146. 146.
    Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D et al. 2018. Comprehensive characterization of cancer driver genes and mutations. Cell 173:371–85.e18
    [Google Scholar]
  147. 147.
    Gerstung M, Jolly C, Leshchiner I, Dentro SC, Gonzalez S et al. 2020. The evolutionary history of 2,658 cancers. Nature 578:122–28
    [Google Scholar]
  148. 148.
    Su Z, Dong S, Zhao SC, Liu K, Tan Y et al. 2021. Novel nanomedicines to overcome cancer multidrug resistance. Drug Resist. Updat. 58:100777
    [Google Scholar]
  149. 149.
    Dong A, Cheung TH. 2021. Deciphering the chromatin organization and dynamics for muscle stem cell function. Curr. Opin. Cell Biol. 73:124–32
    [Google Scholar]
  150. 150.
    Ingram K, Samson SC, Zewdu R, Zitnay RG, Snyder EL, Mendoza MC. 2022. NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity. Oncogene 41:293–300
    [Google Scholar]
  151. 151.
    Nussinov R, Tsai CJ, Jang H. 2022. A new view of activating mutations in cancer. Cancer Res. 82:4114–23
    [Google Scholar]
  152. 152.
    Nussinov R, Tsai CJ, Jang H. 2022. Allostery, and how to define and measure signal transduction. Biophys. Chem. 283:106766
    [Google Scholar]
  153. 153.
    Vasta JD, Peacock DM, Zheng Q, Walker JA, Zhang Z et al. 2022. KRAS is vulnerable to reversible switch-II pocket engagement in cells. Nat. Chem. Biol. 18:596–604
    [Google Scholar]
  154. 154.
    Catalano A, Adlesic M, Kaltenbacher T, Klar RFU, Albers J et al. 2021. Sensitivity and resistance of oncogenic RAS-driven tumors to dual MEK and ERK inhibition. Cancers 13:1852
    [Google Scholar]
  155. 155.
    White E. 2019. Blockade of RAF and autophagy is the one-two punch to take out Ras. PNAS 116:3965–67
    [Google Scholar]
  156. 156.
    Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S et al. 2019. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat. Med. 25:628–40
    [Google Scholar]
  157. 157.
    Carracedo-Reboredo P, Linares-Blanco J, Rodriguez-Fernandez N, Cedron F, Novoa FJ et al. 2021. A review on machine learning approaches and trends in drug discovery. Comput. Struct. Biotechnol. J. 19:4538–58
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-022823-113946
Loading
/content/journals/10.1146/annurev-pharmtox-022823-113946
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error