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Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS–MAPK Reactivation
Open accessPublished version of a preprint
Abstract
Mutant-selective KRASG12C inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in KRASG12C-mutant cancers, including non–small cell lung cancer (NSCLC). However, mechanisms underlying clinical acquired resistance to KRASG12C inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a patient with KRASG12C NSCLC who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes (KRAS, NRAS, BRAF, MAP2K1), all of which converge to reactivate RAS–MAPK signaling. Notably, a novel KRASY96D mutation affecting the switch-II pocket, to which MRTX849 and other inactive-state inhibitors bind, was identified that interferes with key protein–drug interactions and confers resistance to these inhibitors in engineered and patient-derived KRASG12C cancer models. Interestingly, a novel, functionally distinct tricomplex KRASG12C active-state inhibitor RM-018 retained the ability to bind and inhibit KRASG12C/Y96D and could overcome resistance. Significance: In one of the first reports of clinical acquired resistance to KRASG12C inhibitors, our data suggest polyclonal RAS–MAPK reactivation as a central resistance mechanism. We also identify a novel KRAS switch-II pocket mutation that impairs binding and drives resistance to inactive-state inhibitors but is surmountable by a functionally distinct KRASG12C inhibitor. See related commentary by Pinnelli and Trusolino, p. 1874. This article is highlighted in the In This Issue feature, p. 1861
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In the citing paper
“Acquired mutations of NRAS, BRAF, RTK, and MYC were also found in patients treated with sotorasib or adagrasib monotherapy [49, 51, 53, 54].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [54]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Point mutations in the KRAS gene included G12D/F/R/V/W, which prevent covalent interactions with mutant cysteine, as well as V8L, G13D, V14I, Q61H, H95D/Q/R, Y96C, and Y96D [62,97,102,103].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [103]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Multiple mechanisms of acquired resistance have been identified, which largely converge on re-activation of the RAS pathway or alternatively activate parallel signaling pathways such as the PI3K/mTOR pathway10–14.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We and others have recently described mechanisms of acquired resistance in patients with lung and colorectal cancer (CRC) treated with KRASG12C inhibitors, including mutations in KRAS or other RTK–RAS–MAPK pathway effectors, adaptive signaling alterations, and histologic transformation to drug-resistant cell states (14, 18–24).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Vertical reactivation of the RAS pathway elements has been observed in most samples collected from patients who developed resistance to KRASG12C inhibitors.4,8,20,21”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [20]
Experimental — accuracy not yet measured
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In the citing paper
“Genetic alterations, especially secondary RAS mutations, have been identified as one of the most common mechanisms of acquired resistance to KRAS inhibitors in patients [49, 51–55].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [54]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In recent work, a case was described of an acquired Y96D switch II pocket mutation identified at a low variant allele frequency in ctDNA at the time of acquired resistance to adagrasib.23”
From Acquired Resistance to KRAS G12C Inhibition in Cancer (2021) · cites this paper as [23]
The cited source says what the claim attributes to it.
In the citing paper
“Many of the novel mutations were observed at low subclonal frequencies, contributing to tumor heterogeneity [97,103].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [103]
The cited source says what the claim attributes to it.
In the citing paper
“While previous studies have characterized acquired resistance to KRASG12C inhibition and identified causal mutations and non-genetic mechanisms including RTK activation and epithelial-to-mesenchymal transition11–14,35, the mechanisms underlying differential sensitivity to KRASG12C inhibition are less well understood.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“The genetic alterations identified in these studies are highly heterogeneous and may mediate therapeutic resistance via diverse mechanisms, such as changing inhibitor binding affinity, reactivating KRAS activity, and bypassing KRAS-mediated signaling [54, 56].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [54]
The cited source says what the claim attributes to it.
In the citing paper
“Prior studies indicated that tumors with acquired resistance to KRASG12C agents can have multiple resistance mechanisms, including alterations within the RAS/MAPK pathway and bypass activating alterations”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C -mutant Colorectal Cancer (2023) · cites this paper as [29]
In the citing paper
“RM-018 (13), developed by Revolution Medicines, covalently binds to the activated state of KRASG12C mutants, forms a ternary complex with cyclophilin A and KRASG12C, thereby inhibiting their activity.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [81]
In the citing paper
“Meanwhile, RM-018 retained the ability to bind and inhibit KRASG12C/Y96D, thus overcoming drug resistance.81”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [81]
In the citing paper
“Adagrasib is a selective and irreversible oral small-molecule inhibitor of the mutant KRAS G12C protein18 and was recently approved by the FDA for treatment of NSCLC who have received at least 1 prior systemic therapy19.”
From Early Changes in Circulating Cell-Free KRAS G12C Predict Response to Adagrasib in KRAS Mutant Non–Small Cell Lung Cancer Patients (2023) · cites this paper as [18]
In the citing paper
“Nonetheless, there remains an ongoing need for improved clinical outcomes (21), especially since emerging data indicate multiple mechanisms of acquired resistance in patients treated with sotorasib or adagrasib (22–24), many of which involve RAS pathway reactivation.”
In the citing paper
“acquired second-site Y96D mutations in KRASG12C confer clinical resistance to adagrasib by altering the switch 2 pocket such that the inhibitor can no longer bind69.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [69]
In the citing paper
“For example, RM-018 is a covalent KRASG12C inhibitor, but through its interaction with cyclophilin A, targets KRASG12C in the GTP-bound state; hence, RM-018 is a KRASG12C-on inhibitor69.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [69]
In the citing paper
“Pan-KRAS drugs would have advantages versus mutant-selective KRAS drugs in heterogeneous cancers driven by multiple KRAS alterations at baseline or upon development of acquired resistance due to secondary KRAS on-target alterations when compared to mutant-selective inhibitors (Fig. 3), with first examples emerging in the clinic (64–66).”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [65]
In the citing paper
“This has been shown preclinically with the tricomplex KRASG12C active state inhibitor RM-018 in cellular models expressing a KRASG12C Y96D double mutant variant (65).”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [65]
In the citing paper
“Preclinical and clinical data suggest that resistance to KRAS p.G12C inhibition is dependent on receptor tyrosine kinase activity, especially epidermal growth factor receptor (EGFR)-signalling.29 31 32”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [32]
In the citing paper
“correlative studies conducted in other KRASG12C-mutant tumor types treated with these inhibitors have demonstrated the emergence of pleiotropic resistance through both cell autonomous and non-cell autonomous mechanisms76–78.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [77]
In the citing paper
“Thereby, KRAS (Y96D) conferred resistance to KRAS (G12C) inhibitors in patient-derived KRAS (G12C) xenografts [96].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [96]
In the citing paper
“RM-018, a neoteric KRAS (G12C) active state inhibitor, retains the ability to inhibit KRAS (G12C/Y96D) and may address the problem of drug resistance [96].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [96]
In the citing paper
“Recently, a novel KRAS (Y96D) mutation was found, which affects the switch-II pocket and reduces the H-bonding between the Y96 residue of KRAS and MRTX849.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [96]
In the citing paper
“It binds cyclophilin A, and this binary complex can associate with the active state of KRAS G12C and form a covalent bond.”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [113]
In the citing paper
“Interestingly, KRAS Y96D confers resistance to currently approved (non-gluelike) covalent KRAS G12C inhibitors, and RM-018 overcomes such KRAS G12C/Y96D -mediated resistance.”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [113]
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Citations
Cites
Berman, H. M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.235 · Cited by 40,196
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557
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
AACR Project GENIE: Powering Precision Medicine through an International Consortium
The AACR Project GENIE Consortium, The AACR Project GENIE Consortium, André, F., Arnedos, M., Baras, A. S., Baselga, J., Bedard, P. L., Berger, M. F., Bierkens, M., Calvo, F., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0151 · Cited by 1,964
KRAS G12C 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
The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers
Sondka, Z., Bamford, S., Cole, C. G., Ward, S. A., Dunham, I., & Forbes, S. A. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0060-1 · Cited by 1,597
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
Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor
Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172
Self-citationAnchored multiplex PCR for targeted next-generation sequencing
Zheng, Z., Liebers, M. R., Zhelyazkova, B. H., Cao, Y., Panditi, D., Lynch, K. D., Chen, J., Robinson, H. E., Shim, H. S., Chmielecki, J., et al. (2014) · Nature Medicine · doi:10.1038/nm.3729 · Cited by 913
Discovery of a Covalent Inhibitor of KRAS G12C (AMG 510) for the Treatment of Solid Tumors
Lanman, B. A., Allen, J. R., Allen, J. G., Amegadzie, A. K., Ashton, K. S., Booker, S. K., Chen, J. J., Chen, N., Frohn, M. J., Goodman, G., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01180 · Cited by 765
Cited by
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Items 101–200 of 529
Breakthrough in RAS targeting with pan-RAS(ON) inhibitors RMC-7977 and RMC-6236
Filis, P., Salgkamis, D., Matikas, A., & Zerdes, I. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.104250 · Cited by 49
Ho, C. S. L., Tüns, A. I., Schildhaus, H., Wiesweg, M., Grüner, B. M., Hegedűs, B., Schüler, M., Schramm, A. R., & Oeck, S. (2021) · European Journal of Cancer · doi:10.1016/j.ejca.2021.10.003 · Cited by 47
Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure
de Jesus, V. H. F., Mathias-Machado, M. C., de Farias, J. P. F., Aruquipa, M. P. S., Jacome, A. A. D. A., & Peixoto, R. D. (2023) · Cancers · doi:10.3390/cancers15205015 · Cited by 51
Targeting KRAS mutant lung cancer: light at the end of the tunnel
Drosten, M., & Barbacid, M. (2021) · Molecular Oncology · doi:10.1002/1878-0261.13168 · Cited by 49
Sotorasib Is a Pan- RAS G12C Inhibitor Capable of Driving Clinical Response in NRAS G12C Cancers
Rubinson, D. A., Tanaka, N., de la Cruz, F. F., Kapner, K. S., Rosenthal, M. H., Norden, B. L., Barnes, H., Ehnstrom, S., Morales-Giron, A. A., Brais, L. K., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-1138 · Cited by 48
Self-citationGenomic Landscapes and Hallmarks of Mutant RAS in Human Cancers
Scharpf, R. B., Balan, A., Ricciuti, B., Fiksel, J., Cherry, C., Wang, C., Lenoue-Newton, M. L., Rizvi, H. A., White, J. R., Baras, A. S., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-1731 · Cited by 45
Shi, J., Chen, Y., Peng, C., Kuang, L., Zhang, Z., Li, Y., & Huang, K. (2022) · ONCOLOGIE · doi:10.32604/oncologie.2022.027545 · Cited by 45
More to the RAS Story: KRAS G12C Inhibition, Resistance Mechanisms, and Moving Beyond KRAS G12C
Lietman, C. D., Johnson, M. L., McCormick, F., & Lindsay, C. R. (2022) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_351333 · Cited by 44
Overcoming KRAS-Mutant Lung Cancer
Luo, J., Ostrem, J. M. L., Pellini, B., Imbody, D., Stern, Y. E., Solanki, H. S., Haura, E. B., & Villaruz, L. C. (2022) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_360354 · Cited by 46
From bench to bedside: current development and emerging trend of KRAS-targeted therapy
Chen, Y., Liu, Q.-P., Xie, H., & Ding, J. (2023) · Acta Pharmacologica Sinica · doi:10.1038/s41401-023-01194-4 · Cited by 45
Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer
Zhang, S. S., & Nagasaka, M. (2021) · Lung Cancer Targets and Therapy · doi:10.2147/lctt.s334623 · Cited by 44
Targeting KRAS G12C with Covalent Inhibitors
Ostrem, J. M. L., & Shokat, K. M. (2021) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-041621-012549 · Cited by 43
Resistance to KRAS G12C Inhibition in Non-small Cell Lung Cancer
Federico, A. D., Ricciotti, I., Favorito, V., Michelina, S. V., Scaparone, P., Metro, G., Giglio, A. D., Pecci, F., Lamberti, G., Ambrogio, C., et al. (2023) · Current Oncology Reports · doi:10.1007/s11912-023-01436-y · Cited by 42
Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer
Kitai, H., Choi, P. H., Yang, Y. C., Boyer, J. A., Whaley, A., Pancholi, P., Thant, C., Reiter, J., Chen, K., Markov, V., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50063-z · Cited by 41
“To this end, we utilized a class of active-state RAS G12C inhibitors which includes the preclinical tool compounds RM-018 and RMC-4998, the latter being more potent and exhibiting oral bioavailability in vivo 13,19 .”
MethodSomsen, B. A., Schellekens, R. J. C., Verhoef, C. J. A., Arkin, M. R., Ottmann, C., Cossar, P. J., & Brunsveld, L. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c12781 · Cited by 42
Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer
Lu, Y., Yang, Y., Zhu, G., Zeng, H., Fan, Y., Guo, F., Xu, D., Wang, B., Chen, D., & Ge, G. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.83026 · Cited by 42
Adamopoulos, C., Cave, D. D., & Papavassiliou, A. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031631 · Cited by 43
Ciepiela, I., Szczepaniak, M., Ciepiela, P., Hińcza, K., Kopczyński, J., Macek, P., Kubicka, K., Chrapek, M., Tyka, M., Góźdź, S. S., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-55139-w · Cited by 42
The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC
Batrash, F., Kutmah, M., & Zhang, J. (2023) · Experimental Hematology and Oncology · doi:10.1186/s40164-023-00453-8 · Cited by 42
Self-citationAdvancements in Protein Kinase Inhibitors: From Discovery to Clinical Applications
Baldi, S., Long, N., Ma, S., Liu, L., Al-Danakh, A., Qin, Y., Deng, X., Xie, J., & Tang, H. (2025) · Research · doi:10.34133/research.0747 · Cited by 44
Emerging landscape of KRAS inhibitors in cancer treatment
Riedl, J. M., Matsubara, H., McNeil, R., Patel, P. S., de la Cruz, F. F., Gulhan, D., & Corcoran, R. B. (2026) · Cancer Cell · doi:10.1016/j.ccell.2026.01.001 · Cited by 41
Self-citationCurrent and emerging concepts for systemic treatment of metastatic colorectal cancer
Steup, C., Kennel, K. B., Neurath, M. F., Fichtner-Feigl, S., & Greten, F. R. (2025) · Gut · doi:10.1136/gutjnl-2025-335412 · Cited by 39
The Therapeutic Landscape for KRAS-Mutated Colorectal Cancers
Tria, S. M., Burge, M. E., & Whitehall, V. L. J. (2023) · Cancers · doi:10.3390/cancers15082375 · Cited by 38
Feng, J., Xiao, X., Xia, X., Min, J., Tang, W., Shi, X., Xu, K., Zhou, G., Li, K., Shen, P., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.07.006 · Cited by 40
BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer
Li, K., Liu, Y., Ding, Y., Zhang, Z., Feng, J., Hu, J., Chen, J., Lian, Z., Chen, Y., Hu, K., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci161308 · Cited by 37
Sudhakar, N., Yan, L., Qiryaqos, F., Engstrom, L. D., Laguer, J., Calinisan, A., Hebbert, A., Waters, L. M., Moya, K., Bowcut, V., et al. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-23-0870 · Cited by 37
Inhibition of ULK1/2 and KRASG12C controls tumor growth in preclinical models of lung cancer
Ghazi, P. C., O’Toole, K. T., Boggaram, S. S., Scherzer, M. T., Silvis, M. R., Zhang, Y., Jagannathan‐Bogdan, M., Smith, B. D., Lozano, G., Flynn, D. L., et al. (2024) · eLife · doi:10.7554/elife.96992 · Cited by 40
Li, C., Liu, Y., Liu, C., Chen, F., Xie, Y., Zeh, H. J., Yu, C., Liu, J., Tang, D., & Kang, R. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adp4986 · Cited by 36
Self-citationTargeting KRAS in PDAC: A New Way to Cure It?
He, Q., Liu, Z., & Wang, J. (2022) · Cancers · doi:10.3390/cancers14204982 · Cited by 39
A single inhibitor for all KRAS mutations
Corcoran, R. B. (2023) · Nature Cancer · doi:10.1038/s43018-023-00615-x · Cited by 36
Self-citationCovalent fragment approaches targeting non-cysteine residues
Csorba, N., Ábrányi‐Balogh, P., & Keserű, G. M. (2023) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.08.014 · Cited by 37
Natural TCRs targeting KRASG12V display fine specificity and sensitivity to human solid tumors
Bear, A. S., Nadler, R. B., O’Hara, M. H., Stanton, K. L., Xu, C. B., Saporito, R., Rech, A. J., Baroja, M. L., Blanchard, T., Elliott, M. H., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci175790 · Cited by 35
Targeting RAS mutants in malignancies: successes, failures, and reasons for hope
Yang, H. S., Zhou, X., Fu, D., Le, C., Wang, J., Zhou, Q., Liu, X., Yuan, Y., Ding, K., & Xiao, Q. (2022) · 癌症：英文版 · doi:10.1002/cac2.12377 · Cited by 38
Lebedev, T. D., Khabusheva, E., Mareeva, S. R., Ivanenko, K. A., Morozov, A. V., Spirin, P., Рубцов, П. М., Snezhkina, A. V., Kudryavtseva, A. V., Sorokin, M., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102226 · Cited by 34
Karimi, N., & Moghaddam, S. J. (2023) · Cells · doi:10.3390/cells12050749 · Cited by 37
KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges
Ceddia, S., Landi, L. M., & Cappuzzo, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169391 · Cited by 35
Direct K-Ras Inhibitors to Treat Cancers: Progress, New Insights, and Approaches to Treat Resistance
Nussinov, R., & Jang, H. (2023) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-022823-113946 · Cited by 32
Cole, M., Anastasiou, P., Lee, C., Yu, X., de Castro, A., Roelink, J., Moore, C., Mugarza, E., Jones, M. L., Valand, K., et al. (2024) · Science Advances · doi:10.1126/sciadv.adl6464 · Cited by 33
A first-in-class EGFR-directed KRAS G12V selective inhibitor
Stanland, L. J., Huggins, H. P., Sahoo, S. S., Porrello, A., Chareddy, Y. S., Azam, S. H., Perry, J. L., Pallan, P. S., Whately, K. M., Edatt, L., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.05.016 · Cited by 34
Conformational Dynamics Allows Sampling of an “Active-like” State by Oncogenic K-Ras-GDP
Grudzien, P. K., Jang, H., Leschinsky, N., Nussinov, R., & Gaponenko, V. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167695 · Cited by 30
Cholangiocarcinoma Targeted Therapies
Ellis, H., Braconi, C., Valle, J. W., & Bardeesy, N. M. (2024) · American Journal Of Pathology · doi:10.1016/j.ajpath.2024.11.005 · Cited by 30
Lokhandwala, J., Smalley, T. B., & Tran, T. H. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1394702 · Cited by 28
Discovery and Characterization of RP03707: A Highly Potent and Selective KRAS G12D PROTAC
Ji, X. L., Li, H., Wu, G., Zhang, Q., He, X., Wu, Y., Zong, B., Xu, X., Liang, C., Wang, B., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00428 · Cited by 28
Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers
Adachi, Y., Kimura, R., Hirade, K., & Ebi, H. (2021) · Cancers · doi:10.3390/cancers13205081 · Cited by 28
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Song, Z., Lou, L., Fan, G., Liu, L., Yang, G., Liu, H., Chan, A. S. C., Zhang, X., & Xiong, X. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114907 · Cited by 28
Molecular dynamics simulations for the structure-based drug design: targeting small-GTPases proteins
Parise, A., Cresca, S., & Magistrato, A. (2024) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2024.2387856 · Cited by 27
Feng, S., Callow, M. G., Fortin, J.-P., Khan, Z., Bray, D., Costa, M., Shi, Z., Wang, W., & Evangelista, M. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2120512119 · Cited by 27
Khan, H. Y., Nagasaka, M., Li, Y., Aboukameel, A., Uddin, M. H., Sexton, R. E., Bannoura, S. F., Mzannar, Y., Hallak, M. N. A., Kim, S. H., et al. (2022) · Cancer Research Communications · doi:10.1158/2767-9764.crc-21-0176 · Cited by 27
Multiple Strategies to Develop Small Molecular KRAS Directly Bound Inhibitors
Zhou, X., Ji, Y., & Zhou, J. (2023) · Molecules · doi:10.3390/molecules28083615 · Cited by 27
Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancerPreprint
Han, J., Xu, J., Liu, Y., Liang, S., LaBella, K. A., Chakravarti, D., Spring, D. J., Xia, Y., & DePinho, R. A. (2023) · Genes & Development · doi:10.1101/gad.351037.123 · Cited by 27
SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition
Song, X., Zhou, Z., Elmezayen, A., Wu, R., Yu, C., Gao, B., Minna, J. D., Westover, K. D., Zeh, H. J., Kroemer, G., et al. (2024) · Science Advances · doi:10.1126/sciadv.adq4274 · Cited by 26
Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment
Long, S.-A., Amparo, A. M., Goodhart, G., Ahmad, S. A., & Waters, A. M. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1402128 · Cited by 31
Innovative design and potential applications of covalent strategy in drug discovery
Tang, T., Luo, J., Zhang, D., Lü, Y., Liao, W., & Zhang, J. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.117202 · Cited by 27
Self-citationTanaka, N., & Ebi, H. (2024) · Cancer Science · doi:10.1111/cas.16441 · Cited by 26
Self-citationCancer neuroscience: signaling pathways and new therapeutic strategies for cancer
Zhang, S., Yuan, L., Lin, P., Yang, G., Zhou, X., Jinfu, X., Wu, M., & Huang, Y. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02364-y · Cited by 29
Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers
Cekani, E., Epistolio, S., Dazio, G., Cefalì, M., Wannesson, L., Frattini, M., & Froesch, P. (2022) · Cancers · doi:10.3390/cancers14174103 · Cited by 27
Keats, M. A., Han, J. J. W., Lee, Y., Lee, C.-S., & Luo, J. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-0592 · Cited by 26
Baltanás, F. C., García‐Navas, R., Rodríguez-Ramos, P., Calzada, N., Cuesta, C., Borrajo, J., Fuentes‐Mateos, R., Juan, A. O.-S., Vidaña, N., Castellano, E., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41583-1 · Cited by 26
Mei, Y., Qin, X., Yang, Z., Song, S., Liu, X., Wu, C., Qian, J., Huang, X., Zhang, Y., & He, W. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.10.003 · Cited by 27
Newell, S., van der Watt, P. J., & Leaner, V. D. (2023) · IUBMB Life · doi:10.1002/iub.2773 · Cited by 25
Advances in the treatment of KRASG12C mutant non–small cell lung cancer
Shaverdashvili, K., & Burns, T. F. (2025) · Cancer · doi:10.1002/cncr.35783 · Cited by 25
Rosen, J. C., Weiss, J., Pham, N., Li, Q., Martins-Filho, S. N., Wang, Y., Tsao, M., & Moghal, N. (2021) · Translational Oncology · doi:10.1016/j.tranon.2021.101179 · Cited by 25
Padmanabhan, J., Saha, B., Powell, C. D., Mo, Q., Perez, B. A., & Chellappan, S. (2021) · Cancers · doi:10.3390/cancers13153906 · Cited by 25
Li, H., Qi, W.-L., Wang, Y., & Meng, L. (2021) · Genes & Diseases · doi:10.1016/j.gendis.2021.08.011 · Cited by 28
Ferroptosis: A Specific Vulnerability of RAS-Driven Cancers?
Andreani, C., Bartolacci, C., & Scaglioni, P. P. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.923915 · Cited by 26
Realgar‑induced KRAS mutation lung cancer cell death via KRAS/Raf/MAPK mediates ferroptosis
Liu, X., Hai, Y., Dong, J., Xu, L., Hou, W., Su, J., Ren, W., & Liu, D. (2022) · International Journal of Oncology · doi:10.3892/ijo.2022.5447 · Cited by 26
Ramalingam, P. S., Priyadharshini, A., Emerson, I. A., & Arumugam, S. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1107128 · Cited by 25
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 26
Ernst, S. M., van Marion, R., Atmodimedjo, P. N., de Jonge, E., Mathijssen, R. H. J., Paats, M. S., de Bruijn, P., Koolen, S. L., von der Thüsen, J. H., Aerts, J. G. J. V., et al. (2024) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2024.04.007 · Cited by 24
Evolution of direct RAS inhibitors: from undruggable target to clinical breakthroughs
Wang, X., Wu, J., Xiao, A., Wang, J., & Tian, J. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02364-0 · Cited by 25
RAS‐targeted cancer therapy: Advances in drugging specific mutations
Liu, C., Ye, D., Yang, H., Chen, X., Su, Z., Li, X., Ding, M., & Liu, Y. (2023) · MedComm · doi:10.1002/mco2.285 · Cited by 25
Sharma, A. K., Pei, J., Yang, Y., Dyba, M. D., Smith, B. D., Rabara, D., Larsen, E. K., Lightstone, F. C., Esposito, D., Stephen, A. G., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.105650 · Cited by 25
Paweletz, C. P., Heavey, G. A., Kuang, Y., Durlacher, E., Kheoh, T., Chao, R. C., Spira, A. I., Leventakos, K., Johnson, M. L., Ou, S.-H. I., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-0795 · Cited by 23
Khan, I., Koide, A., Zuberi, M., Ketavarapu, G., Denbaum, E., Teng, K. W., Rhett, J. M., Spencer-Smith, R., Hobbs, G. A., Camp, E. R., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110322 · Cited by 24
Zhuang, H., Fan, J., Li, M., Zhang, H., Yang, X., Lin, L., Lu, S., Wang, Q., & Liu, Y. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.915512 · Cited by 23
Eliminating oncogenic RAS: back to the future at the drawing board
Steffen, C. L., Kaya, P., Schaffner‐Reckinger, E., & Abankwa, D. (2023) · Biochemical Society Transactions · doi:10.1042/bst20221343 · Cited by 23
Akamatsu, H., Sakata, S., Azuma, K., Yoshioka, H., Uemura, T., Tsuchiya‐Kawano, Y., Esumi, S., Kurosaki, T., Sato, Y., Sakamoto, T., et al. (2025) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2025.01.006 · Cited by 22
Targeting Oncogenic KRAS in Non-Small-Cell Lung Cancer
Sunaga, N., Miura, Y., Kasahara, N., & Sakurai, R. (2021) · Cancers · doi:10.3390/cancers13235956 · Cited by 23
Direct GDP-KRAS G12C inhibitors and mechanisms of resistance: the tip of the iceberg
Rosen, J. C., Sacher, A. G., & Tsao, M. (2023) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359231160141 · Cited by 22
The promise and peril of KRAS G12C inhibitors
Moore, A. R., & Malek, S. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.07.011 · Cited by 22
Farnsworth, D., Inoue, Y., Johnson, F. D., de Rappard-Yuswack, G., Lu, D., Shi, R., Ma, L. I. J., Mattar, M. S., Somwar, R., Ladanyi, M., et al. (2022) · npj Precision Oncology · doi:10.1038/s41698-022-00328-x · Cited by 21
KRAS mutated NSCLC: past, present, and future directions in a rapidly evolving landscape
Frisch, A., Martin, E., Kim, S. Y., Riess, J. W., Sen, T., & Karim, N. A. (2025) · The Oncologist · doi:10.1093/oncolo/oyaf153 · Cited by 24
KRAS and MET in non-small-cell lung cancer: two of the new kids on the ‘drivers’ block
García-Robledo, J. E., Rosell, R., Ruíz-Patiño, A., Sotelo, C., Arrieta, O. G., Zatarain-Barrón, L., Ordóñez‐Reyes, C., Jaller, E., Rojas, L., Russo, A., et al. (2022) · Therapeutic Advances in Respiratory Disease · doi:10.1177/17534666211066064 · Cited by 22
Vaclová, T., Chakraborty, A., Sherwood, J. L., Ross, S. J., Carroll, D. K., Barrett, J. C., Downward, J., & de Bruin, E. C. (2022) · Scientific Reports · doi:10.1038/s41598-022-06369-3 · Cited by 20
Tu, G., Liu, Q., Qiu, Y., Leung, E. L., & Yao, X. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213845 · Cited by 19
The Irreversible FGFR Inhibitor KIN-3248 Overcomes FGFR2 Kinase Domain Mutations
Balasooriya, E. R., Wu, Q., Ellis, H., Zhen, Y., Norden, B. L., Corcoran, R. B., Mohan, A., Martin, E. S., Franovic, A., Tyhonas, J., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-3588 · Cited by 19
Self-citationDaley, B. R., Sealover, N. E., Finniff, B. A., Hughes, J. M., Sheffels, E., Gerlach, D., Hofmann, M. H., Kostyrko, K., LaMorte, J. P., Linke, A. J., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-3256 · Cited by 20
Targeting the ‘Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective
Lam, K. K., Wong, S. H., & Cheah, P. Y. (2023) · Cells · doi:10.3390/cells12040631 · Cited by 19
TEAD Inhibitors Sensitize KRASG12C Inhibitors via Dual Cell Cycle Arrest in KRASG12C-Mutant NSCLC
Tammaccaro, S. L., Prigent, P., Le Bail, J.-C., Dos-Santos, O., Dassencourt, L., Eskandar, M., Buzy, A., Venier, O., Guillemot, J.-C., Veeranagouda, Y., et al. (2023) · Pharmaceuticals · doi:10.3390/ph16040553 · Cited by 18
Steroidal saponins: Natural compounds with the potential to reverse tumor drug resistance (Review)
Cui, A., Liu, H., Liu, X., Zhang, M., Xiao, B., Wang, B., & Yang, J. (2024) · Oncology Letters · doi:10.3892/ol.2024.14719 · Cited by 18
Zhang, F., Wang, B., Wu, M., Zhang, L., & Ji, M. Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1509173 · Cited by 20
Carvalho, L. A. D. C., Shifrin, N. T., Phadke, M. S., Emmons, M. F., Pechuan-Jorge, X., Mbuga, F., Ospina, O. E., Chow, C., Seu, L., Rose, O. L., et al. (2025) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-25-0744 · Cited by 18
Diehl, J. N., Hibshman, P. S., Ozkan‐Dagliyan, I., Goodwin, C. M., Howard, S. V., Cox, A. D., & Der, C. J. (2022) · Advances in cancer research · doi:10.1016/bs.acr.2021.07.008 · Cited by 18
Zhong, J., Bai, H., Wang, Z., Duan, J., Zhuang, W., Wang, D., Wan, R., Xu, J., Fei, K., Ma, Z., et al. (2023) · Frontiers of Medicine · doi:10.1007/s11684-022-0976-4 · Cited by 19
Khan, H. Y., Nagasaka, M., Aboukameel, A., Alkhalili, O. A., Uddin, M. H., Bannoura, S. F., Mzannar, Y., Azar, I. H., Beal, E. W., Tobon, M. E., et al. (2023) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-23-0251 · Cited by 18
Targeting RAF dimers in RAS mutant tumors: From biology to clinic
Yin, H., Tang, Q., Xia, H., & Bi, F. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.02.018 · Cited by 18
Izumi, M., Costa, D. B., & Kobayashi, S. S. (2024) · Lung Cancer · doi:10.1016/j.lungcan.2024.107885 · Cited by 20
Contreras, C. T., Falke, J. D., Seifert, D., Schneider, C., Krauß, L., Fang, X., Müller, D., Demirdizen, E., Spitzner, M., Oliveira, T. D., et al. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13725 · Cited by 18
Mahran, R., Kapp, J. N., Valtonen, S., Champagne, A., Ning, J., Gillette, W., Stephen, A. G., Hao, F., Plückthun, A., Härmä, H., et al. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.4c00315 · Cited by 20
Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies
Khan, S. U., Budamagunta, V., & Zhou, D. (2023) · Advances in cancer research · doi:10.1016/bs.acr.2023.02.004 · Cited by 21
Metadata
- Authors
- Tanaka, N., Lin, J. J., Li, C., Ryan, M. B., Zhang, J., Kiedrowski, L. A., Michel, A. G., Syed, M. U., Fella, K. A., Sakhi, M., Baiev, I., Juric, D., Gainor, J. F., Klempner, S. J., Lennerz, J. K., Siravegna, G., Bar-Peled, L., Hata, A. N., Heist, R. S., & Corcoran, R. B.
- Affiliations
- Harvard University (US)
- Guardant (United States) (US)
- Massachusetts General Hospital (US)
- 1Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
- Corresponding author
- Hata, Aaron N.
- Heist, Rebecca S.
- Corcoran, Ryan B.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2021-04-06
- Volume
- 11
- Issue
- 8
- Pages
- 1913-1922
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8338755
- OpenAlex
- W3142010099
- Cited by
- 527
- References
- 29
- Citations by year
- 2026: 85 · 2025: 100 · 2024: 124 · 2023: 91 · 2022: 86 · 2021: 41
- FWCI
- 26.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Revolution Medicines (RM-018)
- Stand Up To Cancer—American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17–15)
- NIH (R01-CA164273, 1F32CA250231–01)
- AACR (19–20–45-BARP)
- Damon Runyon (DRR-62–20)
- NIH NCI (R00 CA215249)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C, acquired drug resistance, switch-II pocket, adagrasib, sotorasib, non-small cell lung cancer, NRAS, BRAF, MEK1, drug-protein binding
- MeSH terms
- Acetonitriles, Aged, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Neoplasm Metastasis, Piperazines, Pyridines, Pyrimidines, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm
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