Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS–MAPK Reactivation
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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 found in patients treated with sotorasib or adagrasib monotherapy.
“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]
The Results section reports acquired NRAS and BRAF mutations in one patient after treatment with MRTX849 (adagrasib). It does not report acquired RTK or MYC mutations, or mutations acquired by a patient treated with sotorasib; its clinical resistance case concerns adagrasib alone. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPoint mutations in KRAS that confer resistance include G12D/F/R/V/W, V8L, G13D, V14I, Q61H, H95D/Q/R, Y96C, and Y96D.
“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]
The Results section (page unavailable) identifies G13D and G12V as acquired KRAS mutations against which G12C-selective inhibitors are ineffective, and describes G12F only as a possible mutation that could not be confirmed. The Results and Discussion establish that Y96D confers resistance. Our copy does not substantiate the remaining listed variants or show that every G12 substitution listed prevents covalent binding. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMultiple mechanisms of acquired resistance to KRASG12C inhibitors have been identified, largely converging on reactivation of the RAS pathway or activation of parallel signaling pathways such as PI3K/mTOR.
“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]
The Results and Discussion (page not provided) describe ten acquired-resistance alterations in one patient, all converging on RAS–MAPK reactivation. The paper does not report PI3K/mTOR activation as an alternative acquired-resistance mechanism, and its single-patient findings do not establish the broader distribution of mechanisms implied by the sentence. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMechanisms of acquired resistance in patients with lung and colorectal cancer treated with KRASG12C inhibitors include mutations in KRAS or other RTK-RAS-MAPK pathway effectors, adaptive signaling alterations, and histologic transformation to drug-resistant cell states.
“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]
The Results section (“Heterogeneous acquired resistance alterations converge on RAS-MAPK reactivation”; page not available) describes acquired KRAS, NRAS, BRAF, and MAP2K1 mutations in one patient with non-small cell lung cancer treated with MRTX849. This supports the mutation component, but the paper does not report acquired resistance in a colorectal cancer patient or histologic transformation. Its Introduction discusses adaptive pathway feedback as a mechanism of primary resistance, not clinical acquired resistance. (LLM, conf=0.86)
Experimental — accuracy not yet measuredVertical reactivation of RAS pathway elements has been observed in most samples from patients who developed resistance to KRASG12C inhibitors.
“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]
The Introduction and Discussion report RAS–MAPK reactivation associated with acquired resistance, but this paper studies one patient, not most samples from patients who developed resistance. The authors also describe the resistance alterations as converging on, or predicted to converge on, pathway reactivation; they say additional patients must be studied. Page numbers are not provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Secondary RAS mutations and other genetic alterations are one of the most common mechanisms of acquired resistance to KRAS inhibitors in patients.
“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]
The Results describe secondary KRAS and NRAS mutations, alongside other genetic alterations, emerging after KRASG12C inhibitor treatment in one patient. The Discussion says these alterations suggest RAS–MAPK reactivation may be a common mechanism, but it does not establish that secondary RAS mutations or genetic alterations are among the most common mechanisms across patients; it explicitly calls for analysis of additional patients. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA recent case described an acquired Y96D switch II pocket mutation at low variant allele frequency in ctDNA at the time of acquired resistance to adagrasib.
“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 <sup>G12C</sup> Inhibition in Cancer (2021) · cites this paper as [23]
Many novel mutations were observed at low subclonal frequencies, contributing to tumor heterogeneity.
“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 mechanisms underlying differential sensitivity to KRASG12C inhibition are less well understood.
“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 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.
“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]
Tumors with acquired resistance to KRASG12C agents can have multiple resistance mechanisms, including alterations within the RAS/MAPK pathway and bypass activating alterations.
“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 <i>KRASG12C</i> -mutant Colorectal Cancer (2023) · cites this paper as [29]
RM-018 covalently binds to the activated state of KRASG12C mutants, forms a ternary complex with cyclophilin A and KRASG12C, and thereby inhibits their activity.
“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]
RM-018 retained the ability to bind and inhibit KRASG12C/Y96D, thus overcoming drug resistance.
“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]
Adagrasib is an oral small molecule that selectively and irreversibly inhibits mutant KRAS G12C, and the FDA recently approved it for NSCLC after at least one prior systemic therapy.
“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 <i>KRAS</i> G12C Predict Response to Adagrasib in KRAS Mutant Non–Small Cell Lung Cancer Patients (2023) · cites this paper as [18]
There remains an ongoing need for improved clinical outcomes, especially since emerging data indicate multiple mechanisms of acquired resistance in patients treated with sotorasib or adagrasib, many involving RAS pathway reactivation.
“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.”
Acquired second-site Y96D mutations in KRASG12C cause clinical resistance to adagrasib by altering the switch 2 pocket so the inhibitor cannot bind.
“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]
RM-018 is a covalent KRASG12C inhibitor that, through cyclophilin A, targets GTP-bound KRASG12C and is therefore a KRASG12C-on inhibitor.
“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]
Pan-KRAS drugs would have advantages over mutant-selective drugs in heterogeneous cancers with multiple KRAS alterations at baseline or acquired resistance due to secondary KRAS on-target alterations.
“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 <i>KRAS</i> Mutants (2022) · cites this paper as [65]
The tricomplex KRASG12C active state inhibitor RM-018 has shown preclinical activity in cellular models expressing a KRASG12C Y96D double mutant variant.
“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 <i>KRAS</i> Mutants (2022) · cites this paper as [65]
Preclinical and clinical data suggest that resistance to KRAS p.G12C inhibition is dependent on receptor tyrosine kinase activity, especially EGFR-signalling.
“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]
Correlative studies in other KRASG12C-mutant tumor types treated with these inhibitors demonstrated pleiotropic resistance through cell-autonomous and non-cell-autonomous mechanisms.
“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]
KRAS (Y96D) conferred resistance to KRAS (G12C) inhibitors in patient-derived KRAS (G12C) xenografts.
“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]
RM-018 retains the ability to inhibit KRAS (G12C/Y96D) and may address the problem of drug resistance.
“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]
KRAS (Y96D) mutation affects the switch-II pocket and reduces the H-bonding between the Y96 residue of KRAS and MRTX849.
“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]
RM-018 binds cyclophilin A, and this binary complex associates with active KRAS G12C and forms a covalent bond.
“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]
RM-018 overcomes KRAS G12C/Y96D-mediated resistance to approved covalent KRAS G12C inhibitors.
“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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BackgroundMolecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer
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Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer
Skoulidis, F., Li, B. T., Langen, A. J. D., Hong, D. S., Léna, H., Wolf, J., Dy, G. K., Fontecedro, A. C., Tomasini, P., Velcheti, V., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-03732-5 · Cited by 54 · see citing works
Precision oncology provides opportunities for targeting KRAS-inhibitor resistance
Sattler, M., Mohanty, A., Kulkarni, P., & Salgia, R. (2023) · Trends in Cancer · doi:10.1016/j.trecan.2022.10.001 · Cited by 54 · see citing works
Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas
Salmón, M., Álvarez-Díaz, R., Fustero-Torre, C., Brehey, O., Lechuga, C. G., Sanclemente, M., Fernández-García, F., López-García, A., Martín-Guijarro, M. C., Rodríguez-Perales, S., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci164413 · Cited by 52 · see citing works
Ryan, M. B., Quade, B., Schenk, N., Fang, Z., Zingg, M., Cohen, S. E., Swalm, B. M., Li, C., Özen, A., Ye, C., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0139 · Cited by 51 · see citing works
Self-citationKoga, T., Suda, K., & Mitsudomi, T. (2022) · Cancer Science · doi:10.1111/cas.15263 · Cited by 50 · see citing works
Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver
Ros, J., Vaghi, C., Baraibar, I., Gonzalez, N. S., Rodríguez-Castells, M., García, A., Alcaráz, A., Salvà, F., Tabernero, J. M., & Élez, E. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063304 · Cited by 50 · see citing works
Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies
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- 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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