Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a therapeutic target
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 RAPGEF3<sup>high</sup> PDXs. Our findings provide novel mechanistic insights into squamous transition and therapeutic strategy to overcome EGFR TKI resistance in lung cancer.
Authors
- Cai‐Guang Yang (ORCID: https://orcid.org/0000-0001-5778-4422)
- Luonan Chen (ORCID: https://orcid.org/0000-0002-3960-0068)
- Kwok‐Kin Wong (ORCID: https://orcid.org/0000-0001-6323-235X)
- Qibiao Wu (ORCID: https://orcid.org/0000-0002-1670-1050)
- Xinyuan Tong (ORCID: https://orcid.org/0000-0001-8970-1775)
- Chenchen Guo (ORCID: https://orcid.org/0000-0003-3182-8671)
- Shijie Tang (ORCID: https://orcid.org/0000-0002-8022-0374)
- Weikang Zhu
- Shun Yao (ORCID: https://orcid.org/0000-0003-1727-4078)
- Yayi He (ORCID: https://orcid.org/0000-0002-2820-9119)
- Liang Hu (ORCID: https://orcid.org/0000-0002-0984-9807)
- Xinyun Xie
- Shuo Han (ORCID: https://orcid.org/0000-0003-0760-0183)
- Zhen Qin (ORCID: https://orcid.org/0000-0002-1690-5942)
- Xiaoling Xu (ORCID: https://orcid.org/0000-0003-0618-494X)
- Yueh‐Hung Chou (ORCID: https://orcid.org/0000-0002-1639-3748)
- Hongbin Ji (ORCID: https://orcid.org/0000-0003-0891-6390)
- Shiyu Zhou
- Xue Wang (ORCID: https://orcid.org/0000-0003-3145-9925)
- Yong Wang (ORCID: https://orcid.org/0000-0003-0695-5273)
- Hua Wang (ORCID: https://orcid.org/0009-0006-8533-4991)
Institutions
- Tongji University (CN)
- Chinese Academy of Sciences (CN)
- ShanghaiTech University (CN)
- NYU Langone Health (US)
- National Center for Mathematics and Interdisciplinary Sciences (CN)
- Far Eastern Memorial Hospital (TW)
- Shanghai Institute of Materia Medica (CN)
- Academy of Mathematics and Systems Science (CN)
- Center for Excellence in Molecular Cell Science (CN)
- Hangzhou Academy of Agricultural Sciences (CN)
- Shanghai Pulmonary Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- New York University (US)
Publication Details
- Journal
- National Science Review
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1093/nsr/nwae392
- Citations
- 6
- Primary Topic
- Lung Cancer Treatments and Mutations
- Type
- article
- Field-Weighted Citation Impact
- 2.51
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Science and Technology Commission of Shanghai Municipality
- National Key Research and Development Program of China
- Moonshot Research and Development Program