Overcoming melanoma dual resistance to Vemurafenib and adoptive immunotherapy by chromatin remodeling drug.

BRAFV600E-inhibitors (BRAFi) and modern immune-based therapies have significantly improved the care of melanoma patients. We developed an in vitro model to determine whether tumor resistance mechanisms to this small molecule inhibitor of a driver oncogene and to cytotoxic T lymphocyte (CTL)-delivered apoptotic death signals were exclusive or intersecting. We generated melanoma sublines resistant to BRAFi Vemurafenib and to CTL recognizing the MART-1 melanoma antigen. Vemurafenib-resistant (VemR) sublines were cross-resistant to MART CTL indicating a common apoptotic pathway governing response to both modalities was disrupted. Pretreatment of VemR melanomas with a histone deacetylase inhibitor (HDACi) restored sensitivity to MART CTL apoptosis. These findings suggest that aberrant apoptotic pathways, amenable by a chromatin remodeling drug, regulate tumor resistance mechanisms and identify potential obstacles and solutions for combining these therapies clinically. TModulation of apoptotic machinery by inclusion of HDACi in BRAFV600E targeted therapy protocols as adjuvant will sensitize VemR (also CTL cross-resistant) human melanomas to immunotherapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C143. Citation Format: Ali R. Jazirehi, Ramin Nazarian, Antonio Javier Toress-Collado, James S. Economou. Overcoming melanoma dual resistance to Vemurafenib and adoptive immunotherapy by chromatin remodeling drug. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C143.