{"doi":"10.1158/2159-8290.cd-23-0289","title":"Alveolar Differentiation Drives Resistance to <i>KRAS</i> 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.","journal":"Cancer Discovery","year":2023,"id":318084,"datarank":0.6414999178524083,"base_score":4.276666119016055,"endowment":4.276666119016055,"self_citation_contribution":0.6414999178524083,"citation_network_contribution":0.0,"self_endowment_contribution":0.6414999178524083,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":71,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1024600,"name":"Xueqian Zhuang","orcid":"0000-0001-7012-3223","position":1,"is_corresponding":false},{"id":254930,"name":"Chun‐Hao Pan","orcid":"0000-0002-0776-9408","position":2,"is_corresponding":false},{"id":1024601,"name":"Yan Yan","orcid":"0000-0001-9859-3593","position":3,"is_corresponding":false},{"id":1024602,"name":"Rohit Thummalapalli","orcid":"0000-0002-8865-0299","position":4,"is_corresponding":false},{"id":615193,"name":"Jill Hallin","orcid":"0000-0002-8443-7116","position":5,"is_corresponding":false},{"id":852904,"name":"Stefan Torborg","orcid":"0000-0002-6220-803X","position":6,"is_corresponding":false},{"id":877755,"name":"Anupriya Singhal","orcid":"0000-0001-8816-0065","position":7,"is_corresponding":false},{"id":103683,"name":"Jason C. Chang","orcid":"0000-0002-1705-1870","position":8,"is_corresponding":false},{"id":757106,"name":"Eusebio Manchado","orcid":"0009-0009-3170-9788","position":9,"is_corresponding":false},{"id":237945,"name":"Lukas E. Dow","orcid":"0000-0001-7048-1418","position":10,"is_corresponding":false},{"id":90752,"name":"Rona Yaeger","orcid":"0000-0002-7233-5454","position":11,"is_corresponding":false},{"id":615203,"name":"James G. Christensen","orcid":"0000-0003-1835-0335","position":12,"is_corresponding":false},{"id":218307,"name":"Scott W. Lowe","orcid":"0000-0002-5284-9650","position":13,"is_corresponding":false},{"id":1555,"name":"Charles M. Rudin","orcid":"0000-0001-5204-3465","position":14,"is_corresponding":false},{"id":78291,"name":"Simon Joost","orcid":"0000-0001-6661-541X","position":15,"is_corresponding":false},{"id":14824,"name":"Tuomas Tammela","orcid":"0000-0003-3675-6961","position":16,"is_corresponding":false},{"id":852905,"name":"Zhuxuan Li","orcid":"0009-0001-0051-1586","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:06:55.884740Z","pmid":"37931288","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}