Exploiting Epigenetic Modifiers to Circumvent Melanoma Dual Resistance to TCR-Engineered Immunotherapy- and BRAF^V600E-Kinase Inhibitor

Abstract

The discovery of activating BRAF^V600E mutation in vast majority of melanoma patients has paved the way for novel drug discovery. Targeted therapy using selective BRAF^V600E inhibitor Vemurafenib (PLX4032) and adoptive cell therapy (ACT) using MART-1 T-cell receptor (TCR)-engineered T lymphocytes (F5 CTL) both produce dramatic, but transient, clinical responses in most patients with metastatic melanoma. Adoption of bypass survival signaling pathways (e.g., AKT) and aberrant apoptotic machinery may confer resistance to death signals delivered by Vemurafenib and transgenic CTLs. We have established an in vitro model of resistant (R) lines from F5 CTL- and Vemurafenib-sensitive lines harboring BRAF^V600E under selective pressure. Interestingly, PLX-resistant tumors, while surviving high PLX4032 concentrations, develop cross-resistance to F5 CTL-killing, suggesting the use of a common apoptotic pathway by both modalities. Preliminary experiments suggest that the acquired resistance can be reversed with the histone deacetylase inhibitor (HDACi) SAHA, possibly through modulation of the expression profile of apoptotic genes. Future studies are warranted to identify the bypass signaling pathways and the molecular determinants responsible for immune- and PLX-resistance. Moreover, the exact underlying molecular mechanisms of SAHA-mediated immunosensitization need to be defined. However, these and other studies suggest that the addition of an HDACi to BRAF^V600E-based targeted therapy will immuno-sensitize PLX-resistant metastatic melanomas to F5 CTL ACT.