Sitagliptin, a repurposed diabetes drug, overcomes gemcitabine resistance in pancreatic cancer via ribonucleotide reductase inhibition: SITGEM-CARE phase 2 trial

Gemcitabine resistance remains a major therapeutic barrier in pancreatic ductal adenocarcinoma (PDAC), for which median survival in advanced disease has remained near one year despite extensive clinical investigation. Using artificial intelligence (AI)-guided structure-based drug repurposing, we identified sitagliptin, a DPP-4 inhibitor for diabetes, as a candidate ribonucleotide reductase (RRM1/2) inhibitor that sensitizes PDAC to gemcitabine. Molecular dynamics simulations suggested that sitagliptin disrupts gemcitabine-RRM1/2 interactions, downregulating RRM1/2 expression and restoring chemosensitivity across PDAC cell lines, patient-derived organoids, and mouse models. Sitagliptin enhanced the anti-tumor efficacy of both gemcitabine-nab-paclitaxel (GnP) and FOLFIRINOX regimens in preclinical studies. We conducted SITGEM-CARE, a single-center phase 2 trial in 22 patients with locally advanced or metastatic PDAC (median age 65.0 years; ECOG performance status 1, 86.4%; Stage IV, 68.2%; liver metastases, 54.5%). Patients received sitagliptin 100 mg orally once daily continuously, plus gemcitabine 1000 mg/m² and nab-paclitaxel 125 mg/m² on days 1 and 8 of 21-day cycles. Among 22 evaluable patients, eight achieved a partial response, and 11 had stable disease, yielding an objective response rate of 36.4% (95% CI: 17.2-59.3%) and a disease control rate of 86.4% (95% CI: 65.1-97.1%), with tumor shrinkage in 86.4% of patients. At a median follow-up of 9.9 months, the median progression-free survival was 6.6 months (95% CI: 4.8-12.4) with 6-month and 9-month PFS rates of 63.6% and 43.5%, respectively. Median overall survival was 12.5 months (95% CI: 7.8-not reached), with 62.9% of patients alive at 12 months. Furthermore, treatment was well tolerated, with no Grade 4/5 treatment-related adverse events. These findings are hypothesis-generating and warrant confirmation in adequately powered, randomized trials. ClinicalTrials.gov: NCT05947825.