Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit
Open accessAbstract
Adaptions to therapeutic pressures exerted on cancer cells enable malignant progression of the tumor, culminating in escape from programmed cell death and development of resistant diseases. A common form of cancer adaptation is non-genetic alterations that exploit mechanisms already present in cancer cells and do not require genetic modifications that can also lead to resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is one of the most prevalent mechanisms of adaptive drug resistance and resulting cancer treatment failure, driven by epigenetic reprogramming and EMT-specific transcription factors. A recent breakthrough in cancer treatment is the development of KRAS G12C inhibitors, which herald a new era of therapy by knocking out a unique substitution of an oncogenic driver. However, these highly selective agents targeting KRAS G12C, such as FDA-approved sotorasib (AMG510) and adagrasib (MRTX849), inevitably encounter multiple mechanisms of drug resistance. In addition to EMT, cancer cells can hijack or rewire the sophisticated signaling networks that physiologically control cell proliferation, growth, and differentiation to promote malignant cancer cell phenotypes, suggesting that inhibition of multiple interconnected signaling pathways may be required to block tumor progression on KRAS G12C inhibitor therapy. Furthermore, the tumor microenvironment (TME) of cancer cells, such as tumor-infiltrating lymphocytes (TILs), contribute significantly to immune escape and tumor progression, suggesting a therapeutic approach that targets not only cancer cells but also the TME. Deciphering and targeting cancer adaptions promises mechanistic insights into tumor pathobiology and improved clinical management of KRAS G12C-mutant cancer. This review presents recent advances in non-genetic adaptations leading to resistance to KRAS G12C inhibitors, with a focus on oncogenic pathway rewiring, TME, and EMT.
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Drug-Tolerant Persister (DTP) cells can derive from pre-treatment stochastic expression variability in cell populations, or from treatment-induced changes in transcriptional profiles or epigenetic markers.
“Drug-Tolerant Persister (DTP) cells can derive from pre-treatment stochastic expression variability in cell populations, or from treatment-induced changes in transcriptional profiles or epigenetic markers [115,117,118].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [117]
The Introduction (page unavailable) distinguishes preexisting resistant cancer cells from resistance that develops during treatment, and the Abstract (page unavailable) links adaptive drug resistance through EMT to epigenetic reprogramming and transcription factors. The paper does not identify these cells as drug-tolerant persisters or describe pre-treatment stochastic expression variability; searches for “persister” and “stochastic” found no such passages. (LLM, conf=0.78)
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Cites
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21492 · Cited by 84,109 · see citing works
The basics of epithelial-mesenchymal transition
Kalluri, R., & Weinberg, R. A. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39104 · Cited by 10,196 · see citing works
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261 · see citing works
First-Line Crizotinib versus Chemotherapy in <i>ALK</i> -Positive Lung Cancer
Solomon, B. J., Mok, T., Kim, D.-W., Wu, Y.-L., Nakagawa, K., Mekhail, T., Felip, E., Cappuzzo, F., Paolini, J., Usari, T., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408440 · Cited by 3,190 · see citing works
The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity
Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., et al. (2019) · Nature · doi:10.1038/s41586-019-1694-1 · Cited by 2,277 · see citing works
A Comprehensive Survey of Ras Mutations in Cancer
Prior, I. A., Lewis, P. D., & Mattos, C. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-2612 · Cited by 2,063 · see citing works
Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR
Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., & Bernards, R. (2012) · Nature · doi:10.1038/nature10868 · Cited by 2,051 · see citing works
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works
Sotorasib for Lung Cancers with <i>KRAS</i> p.G12C Mutation
Skoulidis, F., Li, B. T., Dy, G. K., Price, T. J., Falchook, G. S., Wolf, J., Italiano, A., Schuler, M., Borghaei, H., Barlesi, F., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2103695 · Cited by 1,849 · see citing works
KRAS <sup>G12C</sup> Inhibition with Sotorasib in Advanced Solid Tumors
Hong, D. S., Fakih, M. G., Strickler, J. H., Desai, J., Durm, G. A., Shapiro, G. I., Falchook, G. S., Price, T. J., Sacher, A., Denlinger, C. S., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1917239 · Cited by 1,733 · see citing works
Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs
Kris, M. G., Johnson, B. E., Berry, L. D., Kwiatkowski, D. J., Iafrate, A. J., Wistuba, I. I., Varella-Garcia, M., Franklin, W. A., Aronson, S. L., Su, P.-F., et al. (2014) · JAMA · doi:10.1001/jama.2014.3741 · Cited by 1,724 · see citing works
Alsaab, H. O., Sau, S., Alzhrani, R. M., Tatiparti, K., Bhise, K., Kashaw, S. K., & Iyer, A. K. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00561 · Cited by 1,715 · see citing works
Koyama, S., Akbay, E. A., Li, Y. Y., Herter-Sprie, G. S., Buczkowski, K. A., Richards, W. G., Gandhi, L., Redig, A. J., Rodig, S. J., Asahina, H., et al. (2016) · Nature Communications · doi:10.1038/ncomms10501 · Cited by 1,580 · see citing works
Hallin, J., Engstrom, L. D., Hargis, L., Calinisan, A., Aranda, R., Briere, D. M., Sudhakar, N., Bowcut, V., Baer, B. R., Ballard, J. A., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1167 · Cited by 1,304 · see citing works
Acquired Resistance to KRAS <sup>G12C</sup> Inhibition in Cancer
Awad, M. M., Liu, S., Rybkin, I. I., Arbour, K. C., Dilly, J., Zhu, V. W., Johnson, M. L., Heist, R. S., Patil, T., Riely, G. J., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2105281 · Cited by 1,247 · see citing works
Targeting RAS–ERK signalling in cancer: promises and challenges
Samatar, A. A., & Poulikakos, P. I. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4281 · Cited by 1,163 · see citing works
A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene
Luo, J., Emanuele, M. J., Li, D., Creighton, C. J., Schlabach, M. R., Westbrook, T. F., Wong, K.-K., & Elledge, S. J. (2009) · Cell · doi:10.1016/j.cell.2009.05.006 · Cited by 1,017 · see citing works
Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma
Sun, C., Wang, L., Huang, S., Heynen, G. J. J. E., Prahallad, A., Robert, C., Haanen, J., Blank, C., Wesseling, J., Willems, S. M., et al. (2014) · Nature · doi:10.1038/nature13121 · Cited by 888 · see citing works
Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer
Du, B., & Shim, J. S. (2016) · Molecules · doi:10.3390/molecules21070965 · Cited by 805 · see citing works
Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
Lito, P., Solomon, M., Li, L.-S., Hansen, R., & Rosen, N. (2016) · Science · doi:10.1126/science.aad6204 · Cited by 691 · see citing works
The PI3K/AKT/mTOR interactive pathway
Ersahin, T., Tuncbag, N., & Cetin-Atalay, R. (2015) · Molecular BioSystems · doi:10.1039/c5mb00101c · Cited by 683 · see citing works
Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells
Casanova-Acebes, M., Dalla, E., Leader, A. M., Bérichel, J. L., Nikolić, J., Morales, B. M., Brown, M. K., Chang, C., Troncoso, L., Chen, S. T., et al. (2021) · Nature · doi:10.1038/s41586-021-03651-8 · Cited by 599 · see citing works
Riely, G. J., Kris, M. G., Rosenbaum, D., Marks, J., Li, A., Chitale, D. A., Nafa, K., Riedel, E. R., Hsu, M., Pao, W., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0646 · Cited by 578 · see citing works
Myc Cooperates with Ras by Programming Inflammation and Immune Suppression
Kortlever, R. M., Sodir, N. M., Wilson, C. H., Burkhart, D. L., Pellegrinet, L., Brown Swigart, L., Littlewood, T. D., & Evan, G. I. (2017) · Cell · doi:10.1016/j.cell.2017.11.013 · Cited by 553 · see citing works
The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies
Lin, L., Sabnis, A. J., Chan, E., Olivas, V., Cade, L., Pazarentzos, E., Asthana, S., Neel, D., Yan, J. J., Lu, X., et al. (2015) · Nature Genetics · doi:10.1038/ng.3218 · Cited by 551 · see citing works
Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer
Topper, M. J., Vaz, M., Chiappinelli, K. B., DeStefano Shields, C. E., Niknafs, N., Yen, R.-W. C., Wenzel, A., Hicks, J., Ballew, M., Stone, M., et al. (2017) · Cell · doi:10.1016/j.cell.2017.10.022 · Cited by 537 · see citing works
Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor
Hallin, J., Bowcut, V., Calinisan, A., Briere, D. M., Hargis, L., Engstrom, L. D., Laguer, J., Medwid, J., Vanderpool, D., Lifset, E., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-02007-7 · Cited by 533 · cited 1× · see citing works
“Nevertheless, the advent of potent and selective inhibitors for KRAS is definitely not the beginning of the end, but the end of the beginning for the era of precision medicine, as this breakthrough has spurred the search for mutation-specific targeted therapies, as evidenced by the most recent development of KRAS inhi…”
BackgroundEGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer.
Amodio, V., Yaeger, R., Arcella, P., Cancelliere, C., Lamba, S., Lorenzato, A., Arena, S., Montone, M., Mussolin, B., Bian, Y., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0187 · Cited by 504 · see citing works
Diverse alterations associated with resistance to KRAS(G12C) inhibition
Zhao, Y., Murciano-Goroff, Y. R., Xue, J. Y., Ang, A., Lucas, J., Mai, T. T., Da Cruz Paula, A. F., Saiki, A. Y., Mohn, D., Achanta, P., et al. (2021) · Nature · doi:10.1038/s41586-021-04065-2 · Cited by 479 · see citing works
Regulation of cancer cell metabolism: Oncogenic MYC in the driver’s seat
Dong, Y., Tu, R., Liu, H., & Qing, G. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00235-2 · Cited by 405 · see citing works
A combinatorial strategy for treating KRAS-mutant lung cancer
Manchado, E., Weissmueller, S., Morris, J. P., Chen, C.-C., Wullenkord, R., Lujambio, A., de Stanchina, E., Poirier, J. T., Gainor, J. F., Corcoran, R. B., et al. (2016) · Nature · doi:10.1038/nature18600 · Cited by 403 · see citing works
Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer
Labrie, M., Brugge, J. S., Mills, G. B., & Zervantonakis, I. K. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00454-5 · Cited by 388 · see citing works
SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models
Fedele, C., Ran, H., Diskin, B., Wei, W., Jen, J., Geer, M. J., Araki, K., Ozerdem, U., Simeone, D. M., Miller, G., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0444 · Cited by 315 · cited 1× · see citing works
“Similarly, cotargeting MEK and SHP2 intensively blocks RTK-RAS signaling and is superior to inhibiting individual RTKs as RTKs phosphorylate and activate SHP2 and promote signaling from SOS1/2 to RAS (38).”
BackgroundShayan, G., Srivastava, R. M., Li, J., Schmitt, N. C., Kane, L., & Ferris, R. L. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1261779 · Cited by 307 · see citing works
Towards targeting of shared mechanisms of cancer metastasis and therapy resistance
Weiß, F., Lauffenburger, D. A., & Friedl, P. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-021-00427-0 · Cited by 294 · see citing works
PI3K inhibitors in inflammation, autoimmunity and cancer
Stark, A., Sriskantharajah, S., Hessel, E., & Okkenhaug, K. (2015) · Current opinion in pharmacology (Print) · doi:10.1016/j.coph.2015.05.017 · Cited by 266 · see citing works
SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
Fedele, C., Li, S., Teng, K. W., Foster, C. J. R., Peng, D., Ran, H., Mita, P., Geer, M. J., Hattori, T., Koide, A., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201414 · Cited by 265 · see citing works
KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition
Misale, S., Fatherree, J. P., Cortez, E., Li, C., Bilton, S., Timonina, D., Myers, D. T., Lee, D., Gomez-Caraballo, M., Greenberg, M., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0368 · Cited by 259 · see citing works
Adachi, Y., Ito, K., Hayashi, Y., Kimura, R., Tan, T. Z., Yamaguchi, R., & Ebi, H. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2077 · Cited by 249 · see citing works
Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients
Kim, D., Xue, J. Y., & Lito, P. (2020) · Cell · doi:10.1016/j.cell.2020.09.044 · Cited by 239 · see citing works
Breast cancer stem cells: Biology and therapeutic implications
Butti, R., Gunasekaran, V. P., Kumar, T. V. S., Banerjee, P., & Kundu, G. C. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2018.12.001 · Cited by 207 · see citing works
Ricciardi, M., Zanotto, M., Malpeli, G., Bassi, G., Perbellini, O., Chilosi, M., Bifari, F., & Krampera, M. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.29 · Cited by 180 · see citing works
KRAS <sup>G12C</sup> inhibition produces a driver-limited state revealing collateral dependencies
Lou, K., Steri, V., Ge, A. Y., Hwang, Y. C., Yogodzinski, C. H., Shkedi, A. R., Choi, A. L. M., Mitchell, D. C., Swaney, D. L., Hann, B., et al. (2019) · Science Signaling · doi:10.1126/scisignal.aaw9450 · Cited by 175 · see citing works
Briere, D. M., Li, S., Calinisan, A., Sudhakar, N., Aranda, R., Hargis, L., Peng, D. H., Deng, J., Engstrom, L. D., Hallin, J., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0462 · Cited by 168 · see citing works
MAPK pathway activity plays a key role in PD‐L1 expression of lung adenocarcinoma cells
Stutvoet, T. S., Kol, A., de Vries, E. G. E., de Bruyn, M., Fehrmann, R. S. N., van Scheltinga, A. G. T. T., & de Jong, S. (2019) · The Journal of Pathology · doi:10.1002/path.5280 · Cited by 162 · see citing works
Kitai, H., Ebi, H., Tomida, S., Floros, K. V., Kotani, H., Adachi, Y., Oizumi, S., Nishimura, M., Faber, A. C., & Yano, S. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1377 · Cited by 162 · see citing works
An overview of signaling pathways regulating YAP/TAZ activity
Heng, B. C., Zhang, X., Aubel, D., Bai, Y., Li, X., Yan, W., Fussenegger, M., & Deng, X. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03579-8 · Cited by 140 · see citing works
Immunoediting of Cancers May Lead to Epithelial to Mesenchymal Transition
Knutson, K. L., Lu, H., Stone, B. C., Reiman, J. M., Behrens, M. D., Prosperi, C., Gad, E. A., Smorlesi, A., & Disis, M. L. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.3.1526 · Cited by 136 · see citing works
Diepenbruck, M., Waldmeier, L., Ivánek, R., Berninger, P., Arnold, P., van Nimwegen, E., & Christofori, G. (2014) · Journal of Cell Science · doi:10.1242/jcs.139865 · Cited by 132 · see citing works
New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness
Yang, H., Liang, S.-Q., Schmid, R. A., & Peng, R.-W. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00953 · Cited by 129 · see citing works
Self-citationThe Importance of Being PI3K in the RAS Signaling Network
Cuesta, C., Arévalo-Alameda, C., & Castellano, E. (2021) · Genes · doi:10.3390/genes12071094 · Cited by 123 · see citing works
Cell Type–Specific Adaptive Signaling Responses to KRASG12C Inhibition
Solanki, H. S., Welsh, E. A., Fang, B., Izumi, V., Darville, L., Stone, B., Franzese, R., Chavan, S., Kinose, F., Imbody, D., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3872 · Cited by 106 · see citing works
Suzuki, S., Yonesaka, K., Teramura, T., Takehara, T., Kato, R., Sakai, H., Haratani, K., Tanizaki, J., Kawakami, H., Hayashi, H., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0856 · Cited by 105 · see citing works
Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition
Tsai, Y. S., Woodcock, M. G., Azam, S. H., Thorne, L. B., Kanchi, K. L., Parker, J. S., Vincent, B. G., & Pecot, C. V. (2022) · Journal of Clinical Investigation · doi:10.1172/jci155523 · Cited by 103 · see citing works
Lu, H., Liu, C., Velazquez, R., Wang, H., Dunkl, L. M., Kazic-Legueux, M., Haberkorn, A., Billy, E., Manchado, E., Brachmann, S. M., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-0852 · Cited by 90 · cited 1× · see citing works
“A synergistic effect has been observed by dual inhibition of MEK and FGFR1 in genetically engineered mouse models, and an increase in FRS2, the FGFR adaptor protein, has been reported to promote KRAS inhibitor resistance (9, 34).”
BackgroundRapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition
Tsai, Y., Woodcock, M. G., Azam, S. H., Thorne, L. B., Kanchi, K., Parker, J. S., Vincent, B. G., & Pecot, C. V. (2022) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 87 · see citing works
Johnson, M. L., Ou, S. H. I., Barve, M., Rybkin, I. I., Papadopoulos, K. P., Leal, T. A., Velastegui, K., Christensen, J. G., Kheoh, T., Chao, R. C., et al. (2020) · European Journal of Cancer · doi:10.1016/s0959-8049(20)31077-7 · Cited by 77 · see citing works
Kamei, D., Murakami, M., Sasaki, Y., Nakatani, Y., Majima, M., Ishikawa, Y., Ishii, T., Uematsu, S., Akira, S., Hara, S., et al. (2009) · Biochemical Journal · doi:10.1042/bj20090045 · Cited by 70 · see citing works
Sabbatino, F., Wang, Y., Wang, X., Flaherty, K. T., Yu, L. D., Pépin, D., Scognamiglio, G., Pepe, S., Kirkwood, J. M., Cooper, Z. A., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.1878 · Cited by 67 · see citing works
Kim, J. H., Cho, E. B., Lee, J., Jung, O., Ryu, B. J., Kim, S. H., Cho, J. Y., Ryou, C., & Lee, S. Y. (2015) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2015.08.014 · Cited by 61 · see citing works
PD-L1 and immune escape: insights from melanoma and other lineage-unrelated malignancies
Frydenlund, N., & Mahalingam, M. (2017) · Human Pathology · doi:10.1016/j.humpath.2017.06.012 · Cited by 58 · see citing works
Phenotypic plasticity during metastatic colonization
Jehanno, C., Vulin, M., Richina, V., Richina, F., & Bentires‐Alj, M. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.03.007 · Cited by 57 · see citing works
FDA Approves First KRAS Inhibitor: Sotorasib
(2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-nb2021-0362 · Cited by 52 · see citing works
Steinbrunn, T., Stühmer, T., Sayehli, C., Chatterjee, M., Einsele, H., & Bargou, R. C. (2012) · British Journal of Haematology · doi:10.1111/bjh.12039 · Cited by 49 · see citing works
Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again
Abankwa, D., & Gorfe, A. A. (2020) · Biomolecules · doi:10.3390/biom10111522 · Cited by 48 · see citing works
Yang, H., Hall, S. R. R., Sun, B., Zhao, L., Gao, Y., Schmid, R. A., Tan, S. T., Peng, R., & Yao, F. (2021) · Cancers · doi:10.3390/cancers13071561 · Cited by 41 · see citing works
Self-citationBehind the Wheel of Epithelial Plasticity in KRAS-Driven Cancers
Arner, E. N., Du, W., & Brekken, R. A. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01049 · Cited by 38 · see citing works
An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancer
Wang, H., Lv, Q., Xu, Y., Cai, Z., Zheng, J., Cheng, X., Dai, Y., Janne, P. A., Ambrogio, C., & Köhler, J. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.10.012 · Cited by 31 · see citing works
Han, Y., Yu, C.-C., Fine, S. A., Youssof, A. L., Yang, Y., Yan, J., Karg, D. C., Cheung, E. C., Friedman, R. A., Ying, H., et al. (2021) · Oncogene · doi:10.1038/s41388-021-02040-9 · Cited by 27 · see citing works
Small molecule combats cancer-causing KRAS protein at last
Herbst, R. S., & Schlessinger, J. (2019) · Nature · doi:10.1038/d41586-019-03242-8 · Cited by 23 · see citing works
Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS‐mutant cancer
Zhang, Y., Liang, S., Saliakoura, M., Yang, H., Vassella, E., Konstantinidou, G., Tschan, M. P., Hegedűs, B., Zhao, L., Gao, Y., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202013193 · Cited by 23 · see citing works
Self-citationPadhye, A., Konen, J. M., Rodriguez, B. L., Fradette, J. J., Ochieng, J. K., Diao, L., Wang, J., Lü, W., Solis, L. S., Batra, H., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.148392 · Cited by 20 · see citing works
A Breakthrough Brought about by Targeting KRASG12C: Nonconformity Is Punished
Ning, W., Zhang, Y., Kocher, G. J., Dorn, P., & Peng, R. (2022) · Cancers · doi:10.3390/cancers14020390 · Cited by 18 · see citing works
Self-citationCiribilli, Y., & Borlak, J. T. (2017) · Oncotarget · doi:10.18632/oncotarget.21981 · Cited by 17 · see citing works
Xu, X., Xie, K., Li, B., Xu, L., Huang, L., Feng, Y., Pi, C., Zhang, J., Huang, T., Jiang, M., et al. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.108199 · Cited by 14 · see citing works
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KRAS inhibitors: resistance drivers and combinatorial strategies
Isermann, T., Sers, C., Der, C. J., & Papke, B. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.11.009 · Cited by 207 · see citing works
KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance
Ash, L. J., Busia-Bourdain, O., Okpattah, D., Kamel, A., Liberchuk, A., & Wolfe, A. L. (2024) · Current Oncology · doi:10.3390/curroncol31040150 · Cited by 59 · see citing works
“Furthermore, the inhibition of KRAS can activate MRAS in a YAP-dependent manner, leading to a more mesenchymal marker profile [126].”
BackgroundDonahue, K. L., Watkoske, H. R., Kadiyala, P., Du, W., Brown, K. L., Scales, M. K., Elhossiny, A. M., Espinoza, C. E., Opsahl, E. L. L., Griffith, B. D., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0100 · Cited by 58 · see citing works
Kumarasamy, V. M., Frangou, C. G., Wang, J., Wan, Y., Dynka, A., Rosenheck, H. R., Dey, P., Abel, E. V., Knudsen, E. S., & Witkiewicz, A. K. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-2504 · Cited by 56 · see citing works
Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review
Bteich, F., Mohammadi, M., Li, T., Bhat, M. A., Sofianidi, A. A., Wei, N., & Kuang, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512030 · Cited by 32 · see citing works
Activity and resistance to KRASG12C inhibitors in non-small cell lung cancer and colorectal cancer
Ye, W., Lu, X., Qiao, Y., & Ou, W. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189108 · Cited by 25 · see citing works
A novel intranasal peptide vaccine inhibits non-small cell lung cancer with KRAS mutation
Wang, S. H., Cao, Z., Farazuddin, M., Chen, J., Janczak, K. W., Tang, S., Cannon, J., & Baker, J. R. (2024) · Cancer Gene Therapy · doi:10.1038/s41417-023-00717-9 · Cited by 18 · see citing works
Shin, H. Y., Hwang, S., Jeong, J. H., Shin, S. C., Oh, Y., Kim, J. H., Hwang, I., Kim, E. E., Choo, H., & Song, E. J. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107722 · Cited by 11 · see citing works
Morel, M., & Long, W. (2023) · Molecular Oncology · doi:10.1002/1878-0261.13554 · Cited by 9 · see citing works
Adagrasib: a novel inhibitor for KRAS G12C -mutated non-small-cell lung cancer
Guo, M. Z., Marrone, K. A., Spira, A. I., & Rosner, S. (2023) · Future Oncology · doi:10.2217/fon-2022-1106 · Cited by 9 · see citing works
Wang, X., Su, L., Niu, C., Li, X., Wang, R., Li, B., Liu, S., & Xu, Y. (2024) · Drug Development Research · doi:10.1002/ddr.22241 · Cited by 8 · see citing works
Bhattacharya, D., Roman, B., & Reddy, S. (2026) · Cancer Gene Therapy · doi:10.1038/s41417-026-01003-0 · Cited by 9 · see citing works
Xiong, Q., Jin, J., Lin, J., Zhang, B., Jiang, Y., Sun, Z., Zhang, L., Wu, Y., Zhao, G., Qin, J., et al. (2025) · Drug Resistance Updates · doi:10.1016/j.drup.2025.101290 · Cited by 7 · see citing works
Advances in biomarkers of resistance to KRAS mutation-targeted inhibitors
Wang, L., Wei, D., Li, S., & Jiang, S. (2025) · Discover Oncology · doi:10.1007/s12672-025-03569-x · Cited by 7 · see citing works
Lin, Q., Morales-Giron, A. A., Sander, C., Curtis, J. M., Barnes, H., Patel, P. S., de la Cruz, F. F., Riedl, J. M., Matsubara, H., Nakamura, H., et al. (2026) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-25-1788 · Cited by 6 · see citing works
KRAS G12C Inhibitors in the Treatment of Metastatic Colorectal Cancer
Xiao, A., & Fakih, M. (2024) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2024.05.004 · Cited by 5 · see citing works
A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer
Kulkarni, P., Mohanty, A. R., Ramisetty, S. K., Duvivier, H. L., Khan, A., Shrestha, S., Tan, T., Merla, A., El-Hajjaoui, M., Malhotra, J. D., et al. (2023) · Biomolecules · doi:10.3390/biom13111587 · Cited by 4 · see citing works
Rekowska, A. K., Rola, P., Kwiatkowska, A., Wójcik-Superczyńska, M., Gil, M., Krawczyk, P. A., & Milanowski, J. (2024) · Biomedicines · doi:10.3390/biomedicines12020325 · Cited by 3 · see citing works
Emerging Systemic Therapy Considerations for Pancreatic Cancer
Liang, K.-L., Guo, M. Z., & Zaidi, N. (2025) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2025.07.006 · Cited by 2 · see citing works
Megid, R., Ribeiro, G., Gomes, I. N. F., Laus, A. C., Leal, L. F., da Silva, L. S., Ariwoola, A.-B. A., Dias, J. M., Reis, R. M., & Oliveira, R. J. D. S. (2025) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2025.1537523 · Cited by 2 · see citing works
Crouch, S. A. W., Peindl, M., Bencúrová, E., Caliskan, A., Dandekar, T., Dandekar, G., & Breitenbach, T. (2025) · Lung Cancer · doi:10.1016/j.lungcan.2025.108624 · Cited by 1 · see citing works
Yang, P., & Li, Y. (2025) · Investigational New Drugs · doi:10.1007/s10637-025-01514-x · Cited by 1 · see citing works
Chen, X., Keller, S. J., Das, T., Hafner, P., Alrawashdeh, A. Y., Jumaa, H., Chen, T., Besson, S., Norona, J., Schneider, M., et al. (2025) · medRxiv · doi:10.1101/2025.09.09.25335395
Samudrala, R., Bruggemann, L., Falls, Z., & Mahajan, S. D. (2026) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2026.2654614
Chatterjee, S., Arya, S., Sharma, N., Grover, M., Yadav, D., & Parveen, H. (2026) · Medical Oncology · doi:10.1007/s12032-026-03392-6
Mehta, S., Vidhyarthi, Y., Jacquiline, M., & Singh, N. (2026) · Journal of drug targeting · doi:10.1080/1061186x.2026.2741202
Advances in KRASG12D-targeted therapy: from small-molecule inhibitors to PROTACs and molecular glues
Hao, S., Niu, T., Wu, X., Mu, C., Wang, M., Liu, H., & 路海滨 (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110633
王海英, Chen, H., Li, S., & Zhao, J. (2026) · Cancer Innovation · doi:10.1002/cai2.70082
Hamidi, A. A., Moaven, O., Mahmoudian, R. A., & Abbaszadegan, M. R. (2026) · Experimental Hematology and Oncology · doi:10.1186/s40164-026-00849-2
- Authors
- Ning, W., Marti, T. M., Dorn, P., & Peng, R.-W.
- Affiliations
- University of Bern (CH)
- Corresponding author
- Dorn, Patrick
- Peng, Ren-Wang
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2022-11-22
- Volume
- 12
- Pages
- 1004669-1004669
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC9722758
- OpenAlex
- W4309738696
- Cited by
- 29
- References
- 75
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 9 · 2023: 4
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BORIS (University Library Bern) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open Access CRIS of the University of Bern
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (192648, 310030)
- China Scholarship Council
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- KRAS G12C inhibitors, adaptive drug resistance, non-genetic resistance, epithelial-mesenchymal transition, epigenetic reprogramming, sotorasib, adagrasib, tumor microenvironment, tumor-infiltrating lymphocytes, immune evasion, KRAS-mutant cancer
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