Mechanisms of Response and Tolerance to Active RAS Inhibition in KRAS -Mutant Non–Small Cell Lung Cancer
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Abstract
Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the antitumor activity of the RAS(ON) multiselective tricomplex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant non–small cell lung cancer (NSCLC). Broad-spectrum reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse comutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or RASG12C(OFF) inhibitor resistance. Interrogation of time-resolved single-cell transcriptional responses established an in vivo atlas of multimodal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histologic features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies. Significance: Our work reveals robust and durable antitumor activity of the preclinical RAS(ON) multiselective inhibitor RMC-7977 against difficult-to-treat subsets of KRASG12C-mutant NSCLC with primary or acquired RASG12C inhibitor resistance and identifies a conserved mucinous transcriptional state that supports RAS inhibitor tolerance. See related commentary by Marasco and Misale, p. 2018
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In NSCLC, KRAS-mutant tumors evade therapy through transition into AT1-like, squamous, or mucinous states.
“In NSCLC, KRAS-mutant tumors evade therapy through transition into AT1-like,29 squamous,27,28 or mucinous states,29 while pancreatic cancer cells adopt a classical epithelial state to bypass KRAS inhibition.30,31”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [29]
The Results section on mucinous regenerative-homeostatic programs and the Discussion identify a mucinous drug-tolerant state in KRAS-mutant NSCLC. They do not identify an AT1-like state; the paper also says it cannot distinguish expansion of preexisting persister cells from a treatment-induced transition. The squamous-state claim carries different citations (27 and 28), so it is not judged against this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredLineage plasticity is a critical mechanism of non-genetic resistance to KRAS-targeted therapies in NSCLC and PDAC.
“Lineage plasticity has emerged as a critical mechanism of non-genetic resistance to KRAS-targeted therapies in NSCLC and PDAC.27–31”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [29]
The Discussion identifies a mucinous, plasticity-associated drug-tolerant state under RAS inhibition in KRAS-mutant NSCLC, supporting the NSCLC portion. It does not establish lineage plasticity as a resistance mechanism in PDAC; its PDAC discussion concerns other mechanisms. The authors also say they cannot distinguish selection of preexisting persister cells from treatment-induced plasticity. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLineage plasticity has an established role in resistance to KRAS-targeted therapies.
“Despite the established role of lineage plasticity in resistance to KRAS-targeted therapies,26–31 effective therapeutic interventions targeting drivers of lineage plasticity remain lacking.”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [29]
Differentiation into AT1-like, squamous, and mucinous states has been implicated in KRAS inhibitor tolerance in lung adenocarcinoma.
“Differentiation into alveolar type 1 (AT1)-like,26 squamous,27,28 as well as mucinous states29 has been implicated to contribute to KRAS inhibitor tolerance in lung adenocarcinoma, whereas transition into a classical state is observed in PDAC cells surviving KRAS-targeted therapy.30,31”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [29]
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Drilon, A. E. D. C., Sharma, M. R., Johnson, M. L., Yap, T. A., Gadgeel, S. M., Nepert, D. L., Feng, G., Reddy, M. B., Harney, A. S., Elsayed, M., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0361 · Cited by 75 · see citing works
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Prognostic impact of TTF-1 expression in patients with stage IV lung adenocarcinomas
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Immunoengineering can overcome the glycocalyx armour of cancer cells
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The projection score - an evaluation criterion for variable subset selection in PCA visualization
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Elevated Methionine Flux Drives Pyroptosis Evasion in Persister Cancer Cells
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The ImmGen consortium OpenSource T cell project
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Flagged first, then by citations
Cited by
Sorted by citations
Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer
Zhang, Y., Chen, J., She, Y., Fang, Z., Zhang, Y., Ruan, D., Guo, W., Liao, J., Zhou, W., Lao, J., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2025.10.010 · Cited by 23 · see citing works
“In NSCLC, KRAS-mutant tumors evade therapy through transition into AT1-like, 29 squamous, 27,28 or mucinous states, 29 while pancreatic cancer cells adopt a classical epithelial state to bypass KRAS inhibition.”
Differential Response and Resistance to KRAS-Targeted Therapy
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“RMC ‐ 7977 also showed efficacy in NSCLC preclinical models with acquired resistance to sotor-asib/adagrasib [50].”
- Authors
- Araujo, H. A., Pechuan-Jorge, X., Zhou, T., Do, M. T., Hu, X., Rojas Alvarez, F. R., Salvatierra, M. E., Ibarguen, H. P., Lee, R., Raghulan, R., Shah, H., Moreno Ayala, M. A., Chen, K., Tovbis Shifrin, N., Wu, S., Solis Soto, L. M., Negrao, M. V., Gibbons, D. L., Hong, D. S., Roth, J. A., Heymach, J. V., Zhang, J., Jiang, J., Singh, M., Smith, J. A. M., Quintana, E., & Skoulidis, F.
- Affiliations
- 1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Revolution Medicines (United States) (US)
- The University of Texas MD Anderson Cancer Center (US)
- 3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 2Revolution Medicines, Redwood City, California.
- Corresponding author
- Skoulidis, Ferdinandos
- ORCID
- Araujo, Haniel A.
- Pechuan-Jorge, Ximo
- Zhou, Teng
- Do, Minh Truong
- Hu, Xin
- Rojas Alvarez, Frank R.
- Salvatierra, Maria E.
- Ibarguen, Heladio P.
- Lee, Richard
- Raghulan, Rashi
- Shah, Harshit
- Moreno Ayala, Mariela A.
- Chen, Kevin
- Tovbis Shifrin, Nataliya
- Wu, Shuhong
- Solis Soto, Luisa M.
- Negrao, Marcelo V.
- Gibbons, Don L.
- Hong, David S.
- Roth, Jack A.
- Heymach, John V.
- Zhang, Jianjun
- Jiang, Jingjing
- Singh, Mallika
- Smith, Jacqueline A.M.
- Quintana, Elsa
- Skoulidis, Ferdinandos
- Venue
- Cancer Discovery
- Published
- 2024-07-05
- Volume
- 14
- Issue
- 11
- Pages
- 2183-2208
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC12412421
- OpenAlex
- W4400416964
- Semantic Scholar
- e41782f0a7b3b668f5cad675841c24bf53da70d0
- Cited by
- 70
- References
- 83
- Citations by year
- 2026: 29 · 2025: 34 · 2024: 7
- FWCI
- 20.34
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (RP180684)
- National Cancer Institute (1R01 CA262469-01, 1R01 CA279194-01, 1R01 CA279452-01A1, Lung Cancer SPORE P50-CA70907-21, P30 CA016672)
- Rexanna’s Foundation (Tammi Hissom Grant)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C mutation, non-small cell lung cancer, RMC-7977, sotorasib, adagrasib, single-cell transcriptomics, acquired drug resistance, precision oncology
- MeSH terms
- Animals, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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