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Updated: Sep 12, 2025

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

Yijia Zhou1,2, Hua Wang2, Shijie Tang2

  • 1School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

Oncogene
|August 8, 2025
PubMed

Insights

Researchers identified RAPGEF3 as a key driver in basal-subtype lung squamous cell carcinoma (LUSC). Inhibiting RAPGEF3 shows promise for treating LUSC and potentially other cancers by targeting the RAP1A-AKT pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Lung squamous cell carcinoma (LUSC), especially the basal subtype, is a major cause of cancer mortality.
  • Limited therapeutic options and poor survival rates highlight the need for novel treatments for basal-subtype LUSC.

Purpose of the Study:

  • To identify critical molecular drivers of malignant progression in basal-subtype LUSC.
  • To investigate the role of RAPGEF3 and its downstream signaling pathways in LUSC tumorigenesis.
  • To evaluate the therapeutic potential of targeting RAPGEF3 in LUSC.

Main Methods:

  • Analysis of RAPGEF3 expression in basal-subtype LUSC.
  • Investigating the activation of the RAP1A-AKT signaling axis by RAPGEF3.
  • Inhibition of RAPGEF3 using the selective inhibitor ESI-09 in patient-derived xenograft (PDX) models.
  • Comparative analysis of RAP1A and RAP1B roles in tumor cell signaling.

Main Results:

  • RAPGEF3 is significantly upregulated in basal-subtype LUSC.
  • RAPGEF3 activates the RAP1A-AKT pathway, promoting cancer cell proliferation and survival.
  • Inhibition of RAPGEF3 with ESI-09 suppressed tumor growth in PDX models with no significant toxicity.
  • RAP1A, not RAP1B, mediates tumor survival and proliferation via AKT signaling.

Conclusions:

  • RAPGEF3 is a critical driver of malignant progression in basal-subtype LUSC.
  • Targeting RAPGEF3 with ESI-09 represents a promising therapeutic strategy for basal-subtype LUSC.
  • Understanding the distinct roles of RAP1A and RAP1B provides new insights into LUSC pathogenesis and potential therapeutic interventions.
  • RAPGEF3-targeted therapies may extend to other cancers sharing similar oncogenic pathways.

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