Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer

• Published in: Cancer cell Vol. 42; no. 3; pp. 413 - 428.e7
• Main Authors: Tong, Xinyuan, Patel, Ayushi S., Kim, Eejung, Li, Hongjun, Chen, Yueqing, Li, Shuai, Liu, Shengwu, Dilly, Julien, Kapner, Kevin S., Zhang, Ningxia, Xue, Yun, Hover, Laura, Mukhopadhyay, Suman, Sherman, Fiona, Myndzar, Khrystyna, Sahu, Priyanka, Gao, Yijun, Li, Fei, Li, Fuming, Fang, Zhaoyuan, Jin, Yujuan, Gao, Juntao, Shi, Minglei, Sinha, Satrajit, Chen, Luonan, Chen, Yang, Kheoh, Thian, Yang, Wenjing, Yanai, Itai, Moreira, Andre L., Velcheti, Vamsidhar, Neel, Benjamin G., Hu, Liang, Christensen, James G., Olson, Peter, Gao, Dong, Zhang, Michael Q., Aguirre, Andrew J., Wong, Kwok-Kin, Ji, Hongbin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.03.2024
• Subjects: Acetonitriles; adeno-to-squamous transition, AST; Animals; Carcinoma, Squamous Cell; Genes, ras; Humans; KRAS inhibitor; KRT6A; LKB1; Lung Neoplasms; Mice; Mutation; organoid; Piperazines; Proto-Oncogene Proteins p21(ras); Pyrimidines; adeno-to-squamous transition, AST; KRAS inhibitor; LKB1; organoid; KRT6A
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2024.01.012

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer. [Display omitted] •High SCC signature at baseline correlates with poor adagrasib response in KL NSCLC•AST drives resistance to KRAS inhibition in GEMMs and organoid models•ELF5-ΔNp63 axis governs AST process and drug response•AST plasticity signature and KRT6A enrichment predict poor adagrasib responses Tong et al. show that high squamous cell carcinoma (SCC) signature at baseline correlates with poor adagrasib response in patients with KRAS/LKB1-mutant NSCLC. Integrative GEMM and organoid studies demonstrate that adeno-to-squamous transition (AST) drives KRAS inhibitor resistance involving ELF5-mediated epigenetic regulation of ΔNp63. AST plasticity signature and KRT6A predict poor adagrasib response.