DERL3 Predicts and Drives Acquired Sunitinib Resistance in Renal Cell Carcinoma by Suppressing ER...

Background: Sunitinib remains an important VEGFR-targeted therapy for advanced clear cell renal cell carcinoma (ccRCC), but acquired resistance frequently limits its clinical benefit. The molecular mechanisms underlying sunitinib resistance remain insufficiently understood. Methods: Sunitinib-resistant ccRCC models were generated by serial in vivo selection using Caki-1 and 786-O xenografts. Transcriptomic profiling, integration with GSE76068, and siRNA-based screening were performed to identify candidate resistance drivers. DERL3 expression and function were validated using qRT-PCR, Western blot, immunohistochemistry, gain- and loss-of-function assays, xenograft models, and mechanistic analyses of endoplasmic reticulum stress, ROS, and apoptosis. Results: Serial in vivo selection established stable sunitinib-resistant Caki-1-SR and 786-O-SR cells with markedly increased IC50 values. Integrated transcriptomic analysis identified six consistently upregulated genes in resistant models and GSE76068, among which DERL3 knockdown most strongly restored sunitinib sensitivity. DERL3 was upregulated in resistant ccRCC cells and clinical resistant specimens. High intratumoral DERL3 expression was associated with poor response to neoadjuvant sunitinib and shorter progression-free and overall survival. Functionally, DERL3 overexpression increased sunitinib resistance in vitro and in vivo, whereas DERL3 silencing restored drug sensitivity. Mechanistically, DERL3 depletion activated pro-apoptotic endoplasmic reticulum stress, increased ROS accumulation, and enhanced caspase-dependent apoptosis. Suppression of endoplasmic reticulum stress reduced ROS generation and apoptosis induced by DERL3 knockdown. In resistant xenografts, DERL3-targeted inhibition enhanced the antitumor efficacy of sunitinib. Conclusions: DERL3 is a clinically relevant driver of acquired sunitinib resistance in ccRCC. Targeting DERL3 may restore sunitinib sensitivity by reactivating pro-apoptotic endoplasmic reticulum stress and ROS-dependent apoptosis.