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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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“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
“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]
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 measured
The 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 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
“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
“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]
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
“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
“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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Klomp, J. A., Klomp, J. E., Stalnecker, C. A., Bryant, K. L., Edwards, A. C., Drizyte‐Miller, K., Hibshman, P. S., Diehl, J. N., Lee, Y. S., Morales, A. J., et al. (2024) · Science · doi:10.1126/science.adk0775 · Cited by 139
Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development
Huang, F., Han, X., Xiao, X., & Zhou, J. (2022) · Molecules · doi:10.3390/molecules27227728 · Cited by 134
Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors
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KRAS is vulnerable to reversible switch-II pocket engagement in cells
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The New Era of Drug Discovery: The Power of Computer-aided Drug Design (CADD)
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Combinatorial strategies to target RAS-driven cancers
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Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition
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Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance
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Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma
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Self-citationUnveiling the role of KRAS in tumor immune microenvironment
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TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors
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Daraxonrasib in Previously Treated Advanced RAS -Mutated Pancreatic Cancer
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Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS
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A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer
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KRAS G12C Mutations in NSCLC: From Target to Resistance
Addeo, A., Banna, G. L., & Friedlaender, A. (2021) · Cancers · doi:10.3390/cancers13112541 · Cited by 85
Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
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Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer
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Targeting KRAS: from metabolic regulation to cancer treatment
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Drugging the Undruggable: Advances on RAS Targeting in Cancer
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Creating MHC-Restricted Neoantigens with Covalent Inhibitors That Can Be Targeted by Immune Therapy
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The next-generation KRAS inhibitors…What comes after sotorasib and adagrasib?
Oya, Y., Imaizumi, K., & Mitsudomi, T. (2024) · Lung Cancer · doi:10.1016/j.lungcan.2024.107886 · Cited by 73
Sun, R., Hou, Z., Zhang, Y., & Jiang, B. (2022) · Oncology Letters · doi:10.3892/ol.2022.13528 · Cited by 77
Response and Resistance to RAS Inhibition in Cancer
Ebright, R. Y., Dilly, J., Shaw, A. T., & Aguirre, A. J. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-25-0349 · Cited by 76
Riedl, J. M., Fece de la Cruz, F., Lin, J. J., Parseghian, C., Kim, J. E., Matsubara, H., Barnes, H., Caughey, B., Norden, B. L., Morales-Giron, A. A., et al. (2025) · Annals of Oncology · doi:10.1016/j.annonc.2025.01.020 · Cited by 68
Self-citationRAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade
Nokin, M., Mira, A., Patrucco, E., Ricciuti, B., Cousin, S., Soubeyran, I., José, S. S., Peirone, S., Caizzi, L., Michelina, S. V., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51828-2 · Cited by 70
A hybrid quantum computing pipeline for real world drug discovery
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“The key step for quantum computation of molecular properties is to prepare the molecular wave function on a quantum device.”
Backgroundvan Maldegem, F., Valand, K., Cole, M., Patel, H., Angelova, M., Rana, S., Colliver, E., Enfield, K. S. S., Bah, N. K., Kelly, G. P., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26214-x · Cited by 67
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A neomorphic protein interface catalyzes covalent inhibition of RAS G12D aspartic acid in tumors
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KRAS: the Achilles’ heel of pancreas cancer biology
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Stopping the beating heart of cancer: KRAS reviewed
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Resistance to KRASG12C Inhibitors in Non-Small Cell Lung Cancer
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Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies
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KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance
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“These included two processing enzymes involved in membrane targeting, RCE1 and ICMT, as well as RAS pathway members including SHOC2, RAF1, ERK, RSK1, and PREX1 [112].”
BackgroundMolecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer
Wang, Z., Xing, Y., Li, B., Li, X., Liu, B., & Wang, Y. (2022) · Molecular Biomedicine · doi:10.1186/s43556-022-00107-x · Cited by 62
ERK pathway agonism for cancer therapy: evidence, insights, and a target discovery framework
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Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges
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Resistance looms for KRAS G12C inhibitors and rational tackling strategies
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Targeting the undruggable oncogenic KRAS: the dawn of hope
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Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer
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Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas
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Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver
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Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies
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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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