Abstract 2086: Targeting the MNK effector hnRNPA1 enhances the efficacy of BET inhibitors in cancer cells

Abstract

Abstract Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression and are involved in cancer pathogenesis. While a number of BET inhibitors are currently in preclinical development or in early phase clinical trials, BET inhibitors show limited single-agent activity. Thus, there is increasing interest in identifying combination regimens to enhance the efficacy of BET inhibitors. Since MNK kinases can enhance the efficacy of BET inhibitors in vitro and in vivo, in this report we evaluated whether targeting effectors downstream of MNK kinases can enhance the efficacy of BET inhibitors. We show that there is co-expression of the BET protein BRD4 and the MNK effector hnRNPA1 in human tumors. We show that hnRNPA1 knockdown can potentiate the effects of BET inhibitors, with enhanced apoptosis and suppression of proliferation and sphere-forming ability by cancer cells. We also show that the plant flavonoid Quercetin, which reduces hnRNPA1 protein levels in cancer cells, can enhance the efficacy of BET inhibitors. Co-treatment with BET inhibitors and Quercetin results in enhanced apoptosis, further suppression of proliferation, and decreased sphere-forming ability by cancer cells. Significantly, Quercetin synergizes with BET inhibitors at suppressing tumor growth in vivo. Together, these results demonstrate that targeting the MNK effector hnRNPA1 can enhance the efficacy of BET inhibitors, and we identify combination therapy with BET inhibitors and Quercetin for the treatment of cancer patients. Citation Format: Thao Pham, Sophie Stempel, Mario Shields, Christina Spaulding, Krishan Kumar, David Bentrem, Hidayatullah Munshi. Targeting the MNK effector hnRNPA1 enhances the efficacy of BET inhibitors in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2086.