Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer
Year: 2023
Type: preprint
Abstract: 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.
Authors: Xinyuan Tong, Ayushi S. Patel, Eejung Kim, Hongjun Li, Yueqing Chen, Shuai Li, Shengwu Liu, Julien Dilly, Kevin S. Kapner, Yun Xue, Laura 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
Institutions: Chinese Academy of Sciences, Center for Excellence in Molecular Cell Science, State Key Laboratory of Cell Biology, NYU Langone Health, NYU Langone’s Laura and Isaac Perlmutter Cancer Center, New York University, Broad Institute, Brigham and Women's Hospital, Harvard University, Dana-Farber Cancer Institute, Tsinghua University, Chinese Academy of Medical Sciences & Peking Union Medical College, University of Chinese Academy of Sciences, Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, State Key Laboratory of Medical Molecular Biology, Sun Yat-sen University, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Shanghai Medical College of Fudan University, Fudan University, Zhejiang University-University of Edinburgh Institute, Zhejiang University, University of Edinburgh, ShanghaiTech University, Mirati Therapeutics (United States), Center for Systems Biology
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Innovative Research Team of High-level Local University in Shanghai, National Natural Science Foundation of China, Chinese Academy of Sciences, Science and Technology Commission of Shanghai Municipality, Youth Innovation Promotion Association of the Chinese Academy of Sciences, National Key Research and Development Program of China, Youth Innovation Promotion Association, National Cancer Institute
Awards: G1071729081, G1428844090, G1844280166, G2183555972, G2409131717, G3454516728, G3760193292, G3815608915, G4256537512, G4478207000, G4570333008, G5475803762, G5852670985, G6022655854, G6647262531, G7609406742, G7839175125, G8310006906, Mechanisms of response and resistance to KRAS inhibition in pancreatic cancer
OpenAlex ID: W4386616510