作者
Xinyuan Tong,Ayushi Patel,Eejung Kim,Hongjun Li,Yueqing Chen,Shuai Li,Shengwu Liu,Julien Dilly,Kevin S. Kapner,Yun Xue,Laura D. Hover,Suman Mukhopadhyay,Fiona Sherman,Khrystyna Mynzdar,Yijun Gao,Fei Li,Fuming Li,Zhaoyuan Fang,Yujuan Jin,Juntao Gao,Minglei Shi,Luonan Chen,Yang Chen,Thian Kheoh,Wenjing Yang,Itai Yanai,Andre L. Moriera,Vamsidhar Velcheti,Benjamin G. Neel,Liang Hu,James G. Christensen,Peter Olson,Dong Gao,Michael Q. Zhang,Andrew J. Aguirre,Kwok-Kin Wong,Hongbin Ji
摘要
Summary KRAS G12C inhibitors including adagrasib and sortorasib have shown clinical promise in targeting KRAS G12C -mutated lung cancers, however, most patients eventually develop drug resistance. In lung adenocarcinoma patients with co-occurring KRAS G12C and STK11 / LKB1 mutations, we found a high squamous gene signature at baseline significantly correlated with poor adagrasib response. Through integrative studies of Lkb1 -deficient KRAS G12C and Kras G12D lung cancer mouse models and/or organoids treated with KRAS inhibitors, we found tumor cells invoked a lineage plasticity program: adeno-to-squamous transition (AST) that mediated resistance to KRAS inhibition. Transcriptomic and epigenomic analyses revealed ΔNp63 drives AST and modulates response to KRAS inhibition. We identified an intermediate high-plasticity cell state with distinct gene expression program marked by Krt6a upregulation. Notably, higher KRT6A expression at baseline correlated with shorter overall survival in KRAS -mutant patients receiving adagrasib. These data support the role of AST in KRAS inhibitor resistance and provide predictive biomarker for KRAS-targeted therapies in lung cancer.