title: Aberrant apoptotic machinery confers melanoma dual resistance to BRAF(V600E) inhibitor and immune effector cells: immunosensitization by a histone deacetylase inhibitor.
abstract: BRAF(V600E)-inhibitors (BRAFi; e.g., vemurafenib) and modern immune-based therapies such as PD-1/PD-L1 and CTLA-4 checkpoints blockade and adoptive cell transfer (ACT) have significantly improved the care of melanoma patients. Having these two effective (BRAFi and immunotherapy) therapies raises the question whether there is a rational biological basis for using them in combination. We developed an in vitro model to determine whether tumor resistance mechanisms to a small molecule inhibitor of a driver oncogene, and to cytotoxic T lymphocyte (CTL)- and natural killer (NK) cell-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 and NK cells indicating that a common apoptotic pathway governing tumor response to both modalities was disrupted. Pretreatment of VemR melanomas with a histone deacetylase inhibitor (HDACi) restored sensitivity to MART CTL and NK apoptosis by skewing the apoptotic gene programs towards a proapoptotic phenotype. Our in vitro findings suggest that during the course of acquisition of BRAFi resistance, melanomas develop cross-resistance to CTL- and NK-killing. Further, aberrant apoptotic pathways, amenable by an FDA-approved chromatin remodeling drug, regulate tumor resistance mechanisms to immune effector cells. These results may provide rational molecular basis for further investigations to combine these therapies clinically.
authors.affiliation: Department of Surgery, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles 90095, USA.
authors.forename: Ali R
authors.initials: AR
authors.lastname: Jazirehi
authors.affiliation: Department of Medicine, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles 90095, USA.
authors.forename: Ramin
authors.initials: R
authors.lastname: Nazarian
authors.affiliation: Department of Surgery, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles 90095, USA.
authors.forename: Antoni Xavier
authors.initials: AX
authors.lastname: Torres-Collado
authors.affiliation: Department of Surgery, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles 90095, USA ; Department of Microbiology, Immunology and Molecular Genetics, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles 90095, USA ; Department of Molecular and Medical Pharmacology, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles 90095, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Economou
keywords: BRAFV600E kinase inhibitor; HDACi; MAPK; NK cells; SAHA; TCR transgenic CTL; Vemurafenib; adoptive cell transfer; apoptosis; gene expression; immunotherapy; melanoma; sensitization; signal transduction