Prior exposure of pancreatic tumors to [sorafenib + vorinostat] enhances the efficacy of an anti-PD-1 antibody.

ABSTRACT: Checkpoint immunotherapy antibodies have not shown efficacy in pancreatic adenocarcinoma. Pre-clinical studies and subsequently an on-going phase I trial have demonstrated the safety and efficacy of combinatorial radio-chemotherapy plus surgery in this malignancy, including the combination of sorafenib and vorinostat. The lethality of [sorafenib + vorinostat] was enhanced by gemcitabine. Exposure to [sorafenib + vorinostat] reduced the expression of β-catenin, ERBB1, BCL-XL and MCL-1, and the phosphorylation of AKT T308, AKT S473, GSK3 S9/21, mTORC1 and mTORC2. The drug combination increased the expression of Beclin1 and the phosphorylation of eIF2α S51. The drug combination rapidly reduced the levels of multiple HDAC proteins that was directly associated with the previously noted changes

SUBMITTER: Booth L 

PROVIDER: S-EPMC6343728 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature