Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma Journal Article
| 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. |
| Article Title: | Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma |
| 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. ©2023 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 14 |
| Issue: | 2 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-02-01 |
| Start Page: | 308 |
| End Page: | 325 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-23-0289 |
| PUBMED: | 37931288 |
| PROVIDER: | scopus |
| PMCID: | PMC10922405 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Tuomas Tammela -- Source: Scopus |
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