Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma.
Zhuxuan LiXueqian ZhuangChun-Hao PanYan YanRohit ThummalapalliJill HallinStefan R TorborgAnupriya SinghalJason C ChangEusebio ManchadoLukas E DowRona YaegerJames G ChristensenScott W LoweCharles M RudinSimon JoostTuomas TammelaPublished in: Cancer discovery (2023)
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 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 intra-tumoral heterogeneity and suggest targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.
Keyphrases
- wild type
- induced apoptosis
- stem cells
- cell cycle arrest
- signaling pathway
- oxidative stress
- cell death
- type diabetes
- squamous cell carcinoma
- climate change
- young adults
- single cell
- risk assessment
- cell proliferation
- bone marrow
- mesenchymal stem cells
- diabetic rats
- atrial fibrillation
- replacement therapy
- pi k akt
- drug induced
- childhood cancer
- high glucose