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posted on 2024-02-08, 18:46 authored by Zhuxuan Li, Xueqian Zhuang, Chun-Hao Pan, Yan Yan, Rohit Thummalapalli, Jill Hallin, Stefan Torborg, Anupriya Singhal, Jason C. Chang, Eusebio Manchado, Lukas E. Dow, Rona Yaeger, James G. Christensen, Scott W. Lowe, Charles M. Rudin, Simon Joost, Tuomas Tammela Supplementary Table 6 shows the TotalSeqB hashtag oligonucleotide-conjugated antibodies.
Funding
American Cancer Society (ACS)
National Institutes of Health (NIH)
Josie Robertson Scholarship
NIH/NCI cancer center support grant
New York Stem Cell Foundation (NYSCF)
Hope Funds for Cancer Research (HFCR)
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...Medical Scientist Training Program from the NIH
History
ARTICLE 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.
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
