circ-EGFR is a predictor of response to Cetuximab and a potential target in colorectal cancer.

Cetuximab, an EGFR-targeting monoclonal antibody, provides beneficial yet limited clinical improvement in KRAS wild-type metastatic colorectal cancer (mCRC). While circRNA dysregulation has been implicated in various cancers, the role of circ-EGFR in response to EGFR-targeted therapy in mCRC remains largely unexplored. Here, we identified circ-EGFR as a promising predictive biomarker for cetuximab response. Clinically, we first determined that tissue-based circ-EGFR biomarker effectively stratified responders from non-responders to cetuximab in mCRC, with an Area under the Curve (AUC) of 76.8%. Functional assays demonstrated that circ-EGFR enhances the sensitivity to cetuximab, whereas its depletion induces resistance in CRC. Mechanistically, we revealed that circ-EGFR functions as a sponge for miR-942-3p, resulting in the upregulation of GAS1, which activates the Hedgehog signaling pathway and promotes the efficacy of cetuximab in CRC. Importantly, we effectively translated this tissue-based biomarker into a liquid biopsy predictor for anti-EGFR response (AUC: 76.9%), highlighting its non-invasive potential. In conclusion, circ-EGFR is a significant predictor of cetuximab efficacy in mCRC, potentially aiding in patient selection and treatment management, especially for patients with low circ-EGFR expression.