HDACs/mTOR inhibitor synergizes with pyrotinib in HER2-positive pancreatic cancer through degradation of mutant P53

Pancreatic ductal adenocarcinoma (PDAC), as a highly lethal malignancy with high mortality, lacks of effective treatment. Canonical therapeutic targets in PDAC demand further verification among which HER2 receptor tyrosine kinase inhibitor pyrotinib as treatment targets has not be decided. Anti-PDAC efficacy of pyrotinib was evaluated both in vitro and in vivo using both cell lines and patient-derived xenografts. By screening a large-scale library of 1453 compounds, we identified HDACs/mTOR inhibitor 1 as a promising candidate to synergize with pyrotinib. The combination therapy was evaluated in vitro and in vivo in multiple cell lines and animal models. Furthermore, RNA-seq analysis was performed to reveal the latent molecular mechanism of combination therapy. In our study, pyrotinib monotherapy was found to be inefficient to anti-PDAC which exhibited limited anti-proliferation effect in vitro and in vivo. Through therapy combined with HDACs/mTOR inhibitor 1, pyrotinib triggered intense apoptosis in PDAC both in cell lines and animal models. Mechanistic analyses revealed that mutant P53 degradation mediated by HDAC inhibition synergized with HER2 and mTOR inhibition. In conclusion, identification of HDACs/mTOR inhibitor as a synergistic inhibitor, provides a potent therapeutic strategy that targets HER2-positive pancreatic cancer.