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

@article{yu2026sitagliptin,
  title = {{Sitagliptin, a repurposed diabetes drug, overcomes gemcitabine resistance in pancreatic cancer via ribonucleotide reductase inhibition: SITGEM-CARE phase 2 trial.}},
  author = {Jun Yu and Shangheng Shi and Mengyu Li and Qingxiao Fang and Jingrui Yan and Yunfeng Zhang and Ziyun Liu and Zekun Li and Libo Wang and Zongjing Lv and Yadi Wang and Tao Wang and Zhen Zhao and Xiaoqing Ma and Jin Zhang and Guanpeng Xie and Huihui Sun and Ningning Zhao and Antao Chang and Yukuan Feng and Hongwei Wang and Xingyun Chen and Yuexiang Liang and Tiansuo Zhao and Jian Wang and Weidong Ma and Chuntao Gao and Song Gao and Bin Wang and Yongjie Xie and Tianxing Zhou and Chao Yang and Xiuchao Wang and Jihui Hao},
  journal = {Signal transduction and targeted therapy},
  year = {2026},
  month = nov,
  doi = {10.1038/s41392-026-02966-0},
  url = {https://europepmc.org/article/MED/42971953},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - Sitagliptin, a repurposed diabetes drug, overcomes gemcitabine resistance in pancreatic cancer via ribonucleotide reductase inhibition: SITGEM-CARE phase 2 trial.
AU  - Jun Yu
AU  - Shangheng Shi
AU  - Mengyu Li
AU  - Qingxiao Fang
AU  - Jingrui Yan
AU  - Yunfeng Zhang
AU  - Ziyun Liu
AU  - Zekun Li
AU  - Libo Wang
AU  - Zongjing Lv
AU  - Yadi Wang
AU  - Tao Wang
AU  - Zhen Zhao
AU  - Xiaoqing Ma
AU  - Jin Zhang
AU  - Guanpeng Xie
AU  - Huihui Sun
AU  - Ningning Zhao
AU  - Antao Chang
AU  - Yukuan Feng
AU  - Hongwei Wang
AU  - Xingyun Chen
AU  - Yuexiang Liang
AU  - Tiansuo Zhao
AU  - Jian Wang
AU  - Weidong Ma
AU  - Chuntao Gao
AU  - Song Gao
AU  - Bin Wang
AU  - Yongjie Xie
AU  - Tianxing Zhou
AU  - Chao Yang
AU  - Xiuchao Wang
AU  - Jihui Hao
PY  - 2026
DA  - 2026/11/03
JO  - Signal transduction and targeted therapy
DO  - 10.1038/s41392-026-02966-0
UR  - https://europepmc.org/article/MED/42971953
AB  - 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.
SN  - 2095-9907
SN  - 2059-3635
ER  -