Xinyuan Tong, Ayushi S Patel, Eejung Kim, Hongjun Li, Yueqing Chen, Shuai Li, Shengwu Liu, Julien Dilly, Kevin S Kapner, Ningxia Zhang, Yun Xue, Laura Hover, Suman Mukhopadhyay, Fiona Sherman, Khrystyna Myndzar, Priyanka Sahu, Yijun Gao, Fei Li, Fuming Li, Zhaoyuan Fang, Yujuan Jin, Juntao Gao, Minglei Shi, Satrajit Sinha, Luonan Chen, Yang Chen, Thian Kheoh, Wenjing Yang, Itai Yanai, Andre L Moreira, 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
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...
February 20, 2024: Cancer Cell