Drug repositioning of regorafenib for renal cell carcinoma identifies <i>DDR2</i> ‑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. <i>DDR2</i> 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 <i>DDR2</i> 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. <i>In vivo</i>, regorafenib attenuated ACHN tumor growth with a significant difference by day 14. Clinically, higher <i>DDR2</i> associated with inferior overall survival in The Cancer Genome Atlas papillary cohort (KIRP), with no consistent association in the clear cell cohort (KIRC). Across <i>in vitro, in vivo</i>, and <i>in silico</i> analyses, <i>DDR2</i>-high papillary contexts exhibit preferential regorafenib sensitivity, nominating <i>DDR2</i>-enriched papillary RCC for biomarker‑guided repurposing and motivating protein‑level and genetic validation.