Abstract 3684: HDAC inhibitors restore BRAF inhibitor sensitivity by altering PI3K and survival signaling in melanoma

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Abstract Mutations in BRAF activate oncogenic MAPK signaling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signaling.Here we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment. Using patient- and in vivo- derived melanoma cell lines with acquired BRAFi resistance, we show that combined treatment with the BRAFi encorafenib and HDACi panobinostat synergistically induced caspase-dependent apoptotic cell death. HDAC inhibition decreased PI3K pathway activity associated with a reduction in the protein level of a number of receptor tyrosine kinases including AXL, YAP, ERBB2 and ERBB3 but not EGFR or ERBB4. Both NOXA and BIM proteins were implicated as causing cell death, but in a cell line specific manner. Independent of these changes, panobinostat reduced c-Myc and pre-treatment of cells with siRNA against c-Myc reduced BRAFi/HDACi drug-induced cell death. These results suggest that a combination of HDAC and MAPK inhibitors may play a role in treatment of melanoma where the resistance is due to activation of MAPK-independent pathways. This work identifies patients that may respond well to this drug combination and demonstrates the necessity of disrupting multiple cell survival pathways in melanoma. Citation Format: Peter Hersey, Stuart J. Gallagher. HDAC inhibitors restore BRAF inhibitor sensitivity by altering PI3K and survival signaling in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3684.