Rap2B-mediated reprogramming of the PI3K/AKT signaling axis drives resistance to cetuximab-targeted therapy in colorectal carcinoma.

BACKGROUND: Targeted therapy resistance represents a significant clinical challenge in cancer treatment. Rap2B, a member of the Ras superfamily of small GTPases, is frequently overexpressed in various cancers and has been implicated in promoting tumor progression and therapy resistance. However, the role and underlying mechanisms of Rap2B in cetuximab resistance in colorectal cancer (CRC) remain to be elucidated. This study aims to investigate Rap2B expression patterns in CRC models and explore the mechanisms by which Rap2B mediates cetuximab resistance. RESULTS: The expression level of Rap2B in CRC cell lines exhibits a significant negative correlation with sensitivity to cetuximab. In vivo experiments demonstrated that Rap2B downregulation significantly reduced tumor growth and enhanced cetuximab efficacy. Knockdown of Rap2B increases cetuximab sensitivity by inhibiting the PI3K/AKT signaling pathway, resulting in reduced cell proliferation and enhanced apoptosis. Conversely, overexpression of Rap2B induces cetuximab resistance by activating the PI3K/AKT pathway. CONCLUSION: This study highlights a close association between Rap2B overexpression and cetuximab resistance in CRC. The enhanced expression of Rap2B plays a pivotal role in conferring resistance, by activating the PI3K/AKT signaling pathway. Targeting Rap2B or its downstream pathways has the potential to provide novel therapeutic strategies for overcoming cetuximab resistance in colorectal cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12575-025-00303-3.