1. Academic Validation
  2. Imatinib facilitates gemcitabine sensitivity by targeting epigenetically activated PDGFC signaling in pancreatic cancer

Imatinib facilitates gemcitabine sensitivity by targeting epigenetically activated PDGFC signaling in pancreatic cancer

  • Mol Ther. 2022 Nov 15;S1525-0016(22)00662-1. doi: 10.1016/j.ymthe.2022.11.004.
Yin-Hao Shi 1 Qiong-Cong Xu 1 Ying-Qin Zhu 1 Zhi-De Liu 1 Guang-Yin Zhao 2 Qi Liu 1 Xi-Yu Wang 1 Jie-Qin Wang 3 Xiang Xu 1 Qiao Su 2 Jia-Ming Lai 1 Chen-Song Huang 4 Xiao-Yu Yin 5
Affiliations

Affiliations

  • 1 Department of Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
  • 2 Department of Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
  • 3 Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
  • 4 Department of Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. Electronic address: huangchs@mail2.sysu.edu.cn.
  • 5 Department of Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. Electronic address: yinxy@mail.sysu.edu.cn.
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in Cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally high expressed in gemcitabine resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating PDGFR-PI3K-AKT signaling pathway. The PDGFR Inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect in the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.

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