. 2024 Mar 11;42(3):413-428.e7.

doi: 10.1016/j.ccell.2024.01.012. Epub 2024 Feb 22.

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

Xinyuan Tong¹, Ayushi S Patel², Eejung Kim³, Hongjun Li⁴, Yueqing Chen⁵, Shuai Li², Shengwu Liu³, Julien Dilly⁶, Kevin S Kapner⁷, Ningxia Zhang⁸, Yun Xue⁹, Laura Hover¹⁰, Suman Mukhopadhyay², Fiona Sherman², Khrystyna Myndzar², Priyanka Sahu², Yijun Gao¹¹, Fei Li¹², Fuming Li¹³, Zhaoyuan Fang¹⁴, Yujuan Jin¹, Juntao Gao¹⁵, Minglei Shi¹⁶, Satrajit Sinha¹⁷, Luonan Chen¹⁸, Yang Chen¹⁹, Thian Kheoh²⁰, Wenjing Yang²⁰, Itai Yanai²¹, Andre L Moreira², Vamsidhar Velcheti², Benjamin G Neel², Liang Hu¹, James G Christensen²⁰, Peter Olson²⁰, Dong Gao¹, Michael Q Zhang²², Andrew J Aguirre²³, Kwok-Kin Wong²⁴, Hongbin Ji²⁵

Affiliations

¹ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
² Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴ MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, Department of Automation, Tsinghua University, Beijing 100084, China.
⁵ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Biological and biomedical sciences program, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁸ Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China.
⁹ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
¹⁰ Monoceros Biosystems, LLC, San Diego, CA 92129, USA.
¹¹ State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
¹² Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
¹³ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.
¹⁴ Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining 314400, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
¹⁵ Institute for TCM-X, MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, Tsinghua University, Beijing 100084, China.
¹⁶ Institute of Medical Innovation, Peking University Third Hospital, Beijing 100191, China.
¹⁷ Department of Biochemistry, State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14203, USA.
¹⁸ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China; Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China; West China Biomedical Big Data Center, Med-X Center for Informatics, West China Hospital, Sichuan University, Chengdu 610041, China.
¹⁹ State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
²⁰ Mirati Therapeutics, San Diego, CA 92121, USA.
²¹ Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA; Institute of Systems Genetics, New York University Langone Health, New York, NY 10016, USA.
²² Department of Biological Sciences, Center for Systems Biology, The University of Texas, Richardson, TX 75080, USA. Electronic address: michael.zhang@utdallas.edu.
²³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: andrew_aguirre@dfci.harvard.edu.
²⁴ Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA. Electronic address: kwok-kin.wong@nyulangone.org.
²⁵ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China. Electronic address: hbji@sibcb.ac.cn.

PMID: 38402609
DOI: 10.1016/j.ccell.2024.01.012

Free article

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

Xinyuan Tong et al. Cancer Cell. 2024.

Free article

. 2024 Mar 11;42(3):413-428.e7.

doi: 10.1016/j.ccell.2024.01.012. Epub 2024 Feb 22.

Authors

Affiliations

¹ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
² Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴ MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, Department of Automation, Tsinghua University, Beijing 100084, China.
⁵ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Biological and biomedical sciences program, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁸ Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China.
⁹ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
¹⁰ Monoceros Biosystems, LLC, San Diego, CA 92129, USA.
¹¹ State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
¹² Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
¹³ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.
¹⁴ Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining 314400, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
¹⁵ Institute for TCM-X, MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist, Tsinghua University, Beijing 100084, China.
¹⁶ Institute of Medical Innovation, Peking University Third Hospital, Beijing 100191, China.
¹⁷ Department of Biochemistry, State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14203, USA.
¹⁸ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China; Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China; West China Biomedical Big Data Center, Med-X Center for Informatics, West China Hospital, Sichuan University, Chengdu 610041, China.
¹⁹ State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
²⁰ Mirati Therapeutics, San Diego, CA 92121, USA.
²¹ Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA; Institute of Systems Genetics, New York University Langone Health, New York, NY 10016, USA.
²² Department of Biological Sciences, Center for Systems Biology, The University of Texas, Richardson, TX 75080, USA. Electronic address: michael.zhang@utdallas.edu.
²³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: andrew_aguirre@dfci.harvard.edu.
²⁴ Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA. Electronic address: kwok-kin.wong@nyulangone.org.
²⁵ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China. Electronic address: hbji@sibcb.ac.cn.

PMID: 38402609
DOI: 10.1016/j.ccell.2024.01.012

Abstract

KRAS^G12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRAS^G12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRAS^G12C 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 KRAS^G12C and Kras^G12D 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.

Keywords: KRAS inhibitor; KRT6A; LKB1; adeno-to-squamous transition, AST; organoid.

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Conflict of interest statement

Declaration of interests A.J.A. has consulted for Anji Pharmaceuticals, Arrakis Therapeutics, AstraZeneca, Boehringer Ingelheim, Oncorus, Inc., Merck & Co., Inc., Mirati Therapeutics, Nimbus Therapeutics, Plexium, Revolution Medicines, Reactive Biosciences, Riva Therapeutics, Servier Pharmaceuticals, Syros Pharmaceuticals, T-knife Therapeutics. A.J.A. holds equity in Riva Therapeutics. A.J.A. has received research funding from Bristol Myers Squibb, Deerfield, Inc., Eli Lilly, Mirati Therapeutics, Novartis, Novo Ventures, Revolution Medicines, and Syros Pharmaceuticals. K.-K.W. has research funding and/or consulted for Janssen Pharmaceuticals, Pfizer, Bristol Myers Squibb, Zentalis Pharmaceuticals, Blueprint Medicines, Takeda Pharmaceuticals, Mirati Therapeutics, Novartis, Genentech, Merus, Bridgebio Pharma, Xilio Therapeutics, Allerion Therapeutics, Boehringer Ingelheim, Cogent Therapeutics, Revolution Medicines and AstraZeneca.

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

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

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