{ "abstract": "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.", "abstract_shown": true, "affiliations": [ "Pancreas Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. yujun@tjmuch.com.", "National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, State Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. yujun@tjmuch.com.", "Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. yujun@tjmuch.com.", "Clinical Trial Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. yujun@tjmuch.com.", "Clinical Trial Center, Tianjin Cancer Hospital Airport Hospital, Tianjin, China. yujun@tjmuch.com.", "Pancreas Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.", "National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, State Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.", "Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.", "Clinical Trial Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.", "Clinical Trial Center, Tianjin Cancer Hospital Airport Hospital, Tianjin, China.", "Pancreas Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. foxgao2004@163.com.", "National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, State Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. foxgao2004@163.com.", "Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. foxgao2004@163.com.", "Pancreas Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. wangbinpumc@126.com.", "National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, State Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. wangbinpumc@126.com.", "Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. wangbinpumc@126.com.", "Pancreas Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. xieyongjie@tjmuch.com.", "National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, State Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. xieyongjie@tjmuch.com.", "Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. xieyongjie@tjmuch.com.", "Pancreas Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. zhoutianxing@tjmuch.com.", "National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, State Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. zhoutianxing@tjmuch.com.", "Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. zhoutianxing@tjmuch.com.", "Pancreas Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. yangchao@tjmuch.com.", "National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, State Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. yangchao@tjmuch.com.", "Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. yangchao@tjmuch.com.", "Pancreas Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. wangxiuchao2008@163.com.", "National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, State Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. wangxiuchao2008@163.com.", "Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. wangxiuchao2008@163.com.", "Pancreas Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. haojihui@tjmuch.com.", "National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, State Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. haojihui@tjmuch.com.", "Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. haojihui@tjmuch.com." ], "article_type": "research article", "arxiv": null, "author_total": 34, "authors": [ { "affs": [ 0, 1, 2, 3, 4 ], "name": "Jun Yu", "orcid": "0000-0003-3435-6550" }, { "affs": [ 5, 6, 7 ], "name": "Shangheng Shi" }, { "affs": [ 5, 6, 7 ], "name": "Mengyu Li" }, { "affs": [ 5, 6, 7 ], "name": "Qingxiao Fang" }, { "affs": [ 5, 6, 7 ], "name": "Jingrui Yan" }, { "affs": [ 8, 9 ], "name": "Yunfeng Zhang" }, { "affs": [ 5, 6, 7 ], "name": "Ziyun Liu" }, { "affs": [ 5, 6, 7 ], "name": "Zekun Li" }, { "affs": [ 5, 6, 7 ], "name": "Libo Wang" }, { "affs": [ 5, 6, 7 ], "name": "Zongjing Lv" }, { "affs": [ 5, 6, 7 ], "name": "Yadi Wang" }, { "affs": [ 5, 6, 7 ], "name": "Tao Wang" }, { "affs": [ 5, 6, 7 ], "name": "Zhen Zhao" }, { "affs": [ 5, 6, 7 ], "name": "Xiaoqing Ma" }, { "affs": [ 5, 6, 7 ], "name": "Jin Zhang" }, { "affs": [ 5, 6, 7 ], "name": "Guanpeng Xie" }, { "affs": [ 5, 6, 7 ], "name": "Huihui Sun" }, { "affs": [ 5, 6, 7 ], "name": "Ningning Zhao" }, { "affs": [ 5, 6, 7 ], "name": "Antao Chang", "orcid": "0000-0001-9442-619X" }, { "affs": [ 5, 6, 7 ], "name": "Yukuan Feng" }, { "affs": [ 5, 6, 7 ], "name": "Hongwei Wang" }, { "affs": [ 5, 6, 7 ], "name": "Xingyun Chen" }, { "affs": [ 5, 6, 7 ], "name": "Yuexiang Liang" }, { "affs": [ 5, 6, 7 ], "name": "Tiansuo Zhao", "orcid": "0000-0003-1631-6299" }, { "affs": [ 5, 6, 7 ], "name": "Jian Wang" }, { "affs": [ 5, 6, 7 ], "name": "Weidong Ma" }, { "affs": [ 5, 6, 7 ], "name": "Chuntao Gao" }, { "affs": [ 10, 11, 12 ], "name": "Song Gao" }, { "affs": [ 13, 14, 15 ], "name": "Bin Wang" }, { "affs": [ 16, 17, 18 ], "name": "Yongjie Xie" }, { "affs": [ 19, 20, 21 ], "name": "Tianxing Zhou" }, { "affs": [ 22, 23, 24 ], "name": "Chao Yang", "orcid": "0000-0003-3422-2763" }, { "affs": [ 25, 26, 27 ], "name": "Xiuchao Wang", "orcid": "0000-0002-3205-8544" }, { "affs": [ 28, 29, 30 ], "name": "Jihui Hao" } ], "bibtex": "https://research.draconitic.com/paper/7rchh9e5w37g2.bib", "cited_by": 0, "doi": "10.1038/s41392-026-02966-0", "fulltext_url": "https://europepmc.org/articles/PMC13728121", "id": "7rchh9e5w37g2", "issns": [ "2095-9907", "2059-3635" ], "landing_url": "https://europepmc.org/article/MED/42971953", "language": "eng", "licence": "CC-BY-NC-ND", "licence_label": "CC BY-NC-ND", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Article" ], [ "openalex", "2730|Pancreatic and Hepatic Oncology Research" ] ], "openalex": "W7225075640", "pdf_url": "https://europepmc.org/articles/PMC13728121?pdf=render", "pmcid": "PMC13728121", "pmid": "42971953", "published": "2026-11-03", "publisher": "Nature Publishing Group", "ris": "https://research.draconitic.com/paper/7rchh9e5w37g2.ris", "sources": [ { "first_seen": "2026-11-04T15:20:43Z", "native_id": "MED:42971953", "source": "europepmc", "url": "https://europepmc.org/article/MED/42971953" }, { "first_seen": "2026-11-06T12:23:51Z", "native_id": "PMC13728121", "source": "pmc", "url": "https://doi.org/10.1038/s41392-026-02966-0" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2730|Pancreatic and Hepatic Oncology Research", "subfield": "oncology" } ], "title": "Sitagliptin, a repurposed diabetes drug, overcomes gemcitabine resistance in pancreatic cancer via ribonucleotide reductase inhibition: SITGEM-CARE phase 2 trial.", "title_text": "Sitagliptin, a repurposed diabetes drug, overcomes gemcitabine resistance in pancreatic cancer via ribonucleotide reductase inhibition: SITGEM-CARE phase 2 trial.", "type": "peer-reviewed", "updated_at": "2026-11-07T12:21:10Z", "url": "https://research.draconitic.com/paper/7rchh9e5w37g2", "venue": "Signal transduction and targeted therapy", "versions": [] }