Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma
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Abstract
Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but the clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples, we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intratumoral heterogeneity and suggest that targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD. Significance: Treatment resistance limits response to KRAS inhibitors in LUAD patients. We find LUAD residual disease following KRAS targeting is composed of AT1-like cancer cells with the capacity to reignite tumorigenesis. Targeting the AT1-like cells augments responses to KRAS inhibition, elucidating a therapeutic strategy to overcome resistance to KRAS-targeted therapy. This article is featured in Selected Articles from This Issue, p. 201
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Lineage 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 [26]
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 [26]
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“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.”
Self-citation
- Authors
- Li, Z., Zhuang, X., Pan, C.-H., Yan, Y., Thummalapalli, R., Hallin, J., Torborg, S., Singhal, A., Chang, J. C., Manchado, E., Dow, L. E., Yaeger, R., Christensen, J. G., Lowe, S. W., Rudin, C. M., Joost, S., & Tammela, T.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Mirati Therapeutics (United States) (US)
- Novartis (Switzerland) (CH)
- Weill Cornell Medicine (US)
- Corresponding author
- Tammela, Tuomas
- ORCID
- Venue
- Cancer Discovery
- Published
- 2023-11-06
- Volume
- 14
- Issue
- 2
- Pages
- 308-325
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC10922405
- OpenAlex
- W4388406385
- Semantic Scholar
- 8283295c410f4a878addb6f2943f2f8ee67b7779
- Cited by
- 74
- References
- 51
- Citations by year
- 2026: 33 · 2025: 29 · 2024: 10 · 2023: 2
- FWCI
- 13.57
- Type
- journal article
- Language
- en
- Open access
- green
- dx.doi.org
- Locations
- Cancer Discovery (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion)
- Funders
- American Cancer Society
- National Institutes of Health (R01-CA270116)
- Josie Robertson Scholarship
- NIH/NCI cancer center support grant (P30-CA08748)
- New York Stem Cell Foundation (C32559GG)
- Hope Funds for Cancer Research
- National Cancer Institute (F30-CA254120)
- Medical Scientist Training Program from the NIH (T32GM007739)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- lung adenocarcinoma, KRAS inhibition, drug resistance, alveolar differentiation, alveolar type I cells, alveolar type II cells, intratumoral heterogeneity, alveolar stem cells, KRAS mutation, lung injury, KRAS-targeted therapy
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