Targeting MYC sensitizes pancreatic cancer cells to MTOR inhibition. Combination treatment of mTORi with BETi inhibits the Myc network in PDAC

Although PI3K-MTOR is a relevant driver pathway and target in pancreatic ductal adenocarcinoma (PDAC), clinical development of PI3K-MTOR targeting therapies remains unsuccessful. Therefore, resistance and adaption occurring in response to this class of inhibitors must be analyzed to improve the chance for clinical implementation. We investigated the characteristics of MTOR inhibitor (MTORi) resistant human and murine PDACs. We observed that MTORi resistant PDAC are characterized by activity of the MYC network. To test the contribution of MYC towards MTOR inhibitor resistance, we indirectly targeted MYC by bromodomain and extra-terminal motif (BET) protein inhibitors (BETi). We show that a subset of human and murine PDAC cells as well as primary patient-derived organoids revealed a synergistic response towards a combination therapy of MTORi with BETi. Mechanistically, this combination converges on MYC expression to impair cell cycle progression. Therefore, our work points to a novel combination therapy in a PDAC subtype characterized by MYC and MTOR activity.