首页|Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a therapeutic target

Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a therapeutic target

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Although adeno-to-squamous transition(AST)has been observed in association with resistance to epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor(TKI)in clinic,its causality,molecular mechanism and overcoming strategies remain largely unclear.We here demonstrate that squamous transition occurs concomitantly with TKI resistance in PC9-derived xenograft tumors.Perturbation of squamous transition via DNp63 overexpression or knockdown leads to significant changes in TKI responses,indicative of a direct causal link between squamous transition and TKI resistance.Integrative RNA-seq,ATAC-seq analyses and functional studies reveal that FOXA1 plays an important role in maintaining adenomatous lineage and contributes to TKI sensitivity.FOXM1 overexpression together with FOXA1 knockout fully recapitulates squamous transition and TKI resistance in both PC9 xenografts and patient-derived xenograft(PDX)models.Importantly,pharmacological inhibition of RAPGEF3 combined with EGFR TKI efficiently overcomes TKI resistance,especially in RAPGEF3high PDXs.Our findings provide novel mechanistic insights into squamous transition and therapeutic strategy to overcome EGFR TKI resistance in lung cancer.

EGFR-mutant lung canceradeno-to-squamous transitiontyrosine kinase inhibitor resistancetranscription factor networkRAPGEF3

Hua Wang、Shijie Tang、Qibiao Wu、Yayi He、Weikang Zhu、Xinyun Xie、Zhen Qin、Xue Wang、Shiyu Zhou、Shun Yao、Xiaoling Xu、Chenchen Guo、Xinyuan Tong、Shuo Han、Yueh-Hung Chou、Yong Wang、Kwok-Kin Wong、Cai-Guang Yang、Luonan Chen、Liang Hu、Hongbin Ji

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Key Laboratory of Multi-Cell Systems,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

Department of Medical Oncology,Shanghai Pulmonary Hospital,Tongji University Medical School Cancer Institute,Tongji University School of Medicine,Shanghai 200092,China

Center for Excellence in Mathematical Sciences,National Center for Mathematics and Interdisciplinary Sciences,Key Laboratory of Management,Decision and Information System,Hua Loo-Keng Center for Mathematical Sciences,Academy of Mathematics and Systems Science,Chinese Academy of Sciences,Beijing 100190,China

State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China

School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China

Department of Radiation Oncology,Shanghai Pulmonary Hospital,Tongji University School of Medicine,Shanghai 200433,China

Department of Anatomical Pathology,Far Eastern Memorial Hospital,New Taipei City,Taiwan,China

Laura and Isaac Perlmutter Cancer Center,New York University Grossman School of Medicine,NYU Langone Health,NY 10016,USA

School of Life Science and Technology,Shanghai Tech University,Shanghai 201210,China

School of Life Science,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China

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2024

10.1093/nsr/nwae392

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ISSN：
年,卷(期)：2024.11(12)