Drug repositioning of regorafenib for renal cell carcinoma identifies DDR2‑associated sensitivity in ACHN models

Renal cell carcinoma (RCC) is heterogeneous and frequently refractory to cytotoxic therapy. We investigated whether contexts with elevated DDR2-a collagenactivated receptor tyrosine kinase-are preferentially sensitive to regorafenib, a multikinase inhibitor with activity against DDR2. DDR2 mRNA was quantified by quantitative PCR in Caki1 (clear cell), ACHN (papillary), and Caki2 (papillary) relative to HK2. Shortterm viability was assessed by a tetrazolium (MTT) assay with fourparameter logistic fits to estimate the lowest observed effect concentration (LOEC) and halfmaximal inhibitory concentration (IC₅₀). In an ACHN xenograft model, mice were randomized to vehicle or regorafenib (10 mg/kg, intraperitoneally) every 3 days for 21 days. ACHN and Caki1 expressed higher DDR2 than HK2, whereas Caki2 was modest; ACHN xenografts retained elevation, whereas Caki2 xenografts did not. Regorafenib reduced ACHN viability with LOEC 1 μM and IC₅₀ 6.93 μM, while Caki2 first declined at 30 μM without reaching 50% inhibition. In vivo, regorafenib attenuated ACHN tumor growth with a significant difference by day 14. Clinically, higher DDR2 associated with inferior overall survival in The Cancer Genome Atlas papillary cohort (KIRP), with no consistent association in the clear cell cohort (KIRC). Across in vitro, in vivo, and in silico analyses, DDR2-high papillary contexts exhibit preferential regorafenib sensitivity, nominating DDR2-enriched papillary RCC for biomarker‑guided repurposing and motivating protein‑level and genetic validation.