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

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.