2. Academic Validation
  3. Identification of RAPGEF3 as the therapeutic vulnerability of basal-subtype lung squamous cell carcinoma

Identification of RAPGEF3 as the therapeutic vulnerability of basal-subtype lung squamous cell carcinoma

  • Oncogene. 2025 Sep;44(34):3142-3148. doi: 10.1038/s41388-025-03532-8.
Yijia Zhou # 1 2,  Hua Wang # 2,  Shijie Tang 2,  Yayi He 3,  Cai-Guang Yang 4 5,  Luonan Chen 2 6,  Hongbin Ji 7 8 9 10
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 2 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, China.
  • 3 Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 5 University of the Chinese Academy of Sciences, Beijing, China.
  • 6 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  • 7 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. hbji@sibcb.ac.cn.
  • 8 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, China. hbji@sibcb.ac.cn.
  • 9 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. hbji@sibcb.ac.cn.
  • 10 School of Medicine, Westlake University, Hangzhou, China. hbji@sibcb.ac.cn.
  • # Contributed equally.
PMID: 40781157 DOI: 10.1038/s41388-025-03532-8
Abstract

Lung squamous cell carcinoma (LUSC), particularly the basal-subtype, remains a leading cause of cancer-related mortality, with limited therapeutic options and poor survival rates. In this study, we identify RAPGEF3 as a critical driver of malignant progression in basal-subtype LUSC. Our findings show that RAPGEF3 is significantly upregulated in basal-subtype LUSC and plays a pivotal role in tumor progression by activating the RAP1A-AKT signaling axis, essential for cell proliferation and survival. We demonstrate that inhibiting RAPGEF3 with the selective inhibitor ESI-09 significantly suppresses tumor growth in patient-derived xenograft (PDX) models without notable toxicity. Furthermore, our results reveal that RAP1A, rather than its paralog RAP1B, mediates tumor survival and proliferation through Akt signaling, providing new insights into the functional differences between these isoforms. Given the lack of targeted therapies for basal-subtype LUSC, RAPGEF3 emerges as a novel and promising therapeutic target. These findings not only contribute to understanding the molecular mechanisms of basal-subtype LUSC but also suggest that RAPGEF3-targeted therapies may be applicable to Other cancers with similar oncogenic signaling pathways.

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