Project 3 will focus on efforts to understand and overcome acute resistance to BRAF(V600E) suppression in melanoma by understanding how BRAF(V600E) modulates death signals. Multiple studies show that BRAF(V600E) suppression strongly induces BIM, a pro-apoptotic factor. However very little apoptosis occurs. Instead either MCL1 or BCL2A1 bind &sequester BIM. We report BCL2A1 as a newly recognized genomically amplified melanoma oncogene in about 1/3 of patients. It is also transcriptionally regulated by MITF, a lineage specific master transcription factor which is also amplified in ~20% of melanomas. BCL2A1 and MITF are thus lineage-restricted anti-apoptotic regulators. We found that BRAF-MEK-MAPK phosphorylates MITF, triggering ubiquitin-dependent degradation. Conversely BRAF(V600E) suppression blocks MITF degradation, thereby upregulating MITF. In turn MITF's targets are potently induced?some of which are anti-apoptotic while others serve as immune antigens. The immune system may contribute to efficacy of BRAF(V600E) inhibitors because 1) treatment induces T cell tumor infiltrates within 10 days, 2) melanocytic antigen expression is strongly induced via MITF, and 3) BRAF( /600E) targeting is significantly weaker for melanomas in an immunodeficient background. To pursue these questions Aim1 will examine MITF's and BCL2A1's roles as apoptosis antagonists to BRAF inhibitors. We will utilize clinically annotated patient specimens to determine whether genomic amplifications in MITF or BCL2A1 are prognostic for response to BRAF(V600E) targeting. Further, the use of gene targeting (knockdown) suggests that MITF and BCL2A1 are lineage specific antagonists to inhibition of BRAF sensitivity. Therefore several small molecules which antagonize MITF or BCL2A1, and which are clinically available, will be tested alone or with BRAF suppression in vitro, in mice, and (for MITF antagonism) in a recently opened clinical trial.
Aim 2 will dissect interactions between BRAF(V600E), MITF, and melanoma immune responses in immune-intact mice. Inhibitors to BRAF, MEK, or ERK will be combined with immune checkpoint blocking antibodies (anti-CTLA4 anti-PDLI, or anti-PDI) and tested in mice, and in correlative studies for a human trial for vemurafenib+ipilimumab. Distinct vulnerabilities in """"""""resistant"""""""" lines will be analyzed against copy number and deep sequencing data (Project 1, 2 &Cores A, B) and shRNA functional screens (Projects 1 &2) to identify drugable combination pathways for preclinical and clinical development.

Public Health Relevance

The melanoma field has seen significant therapeutic progress, but little durable benefit (cure) from the new, targeted drugs. This Project seeks to improve melanoma therapy by identifying drug combinations and incorporation of immune modulation, which we believe may profoundly enhance the ability to kill melanoma cells upon suppression of BRAF(V600E). Successful implementation of this work will lead to molecular predictors of treatment efficacy and new lead-combinations for clinical development in man.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Eliades, Philip; Abraham, Brian J; Ji, Zhenyu et al. (2018) High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma. J Invest Dermatol 138:1582-1590
Nguyen, Nhu T; Fisher, David E (2018) MITF and UV responses in skin: From pigmentation to addiction. Pigment Cell Melanoma Res :
Kapp, Friedrich G; Perlin, Julie R; Hagedorn, Elliott J et al. (2018) Protection from UV light is an evolutionarily conserved feature of the haematopoietic niche. Nature 558:445-448
Romano, Gabriele; Chen, Pei-Ling; Song, Ping et al. (2018) A Preexisting Rare PIK3CAE545K Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling. Cancer Discov 8:556-567
Wein, Marc N; Foretz, Marc; Fisher, David E et al. (2018) Salt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential. Trends Endocrinol Metab 29:723-735
Levy, Carmit; Golan, Tamar; Fisher, David E (2018) miRNA-211 stops the clock. Noncoding RNA Investig 2:
Byrne, Elizabeth H; Fisher, David E (2017) Immune and molecular correlates in melanoma treated with immune checkpoint blockade. Cancer 123:2143-2153
Lin, William M; Fisher, David E (2017) Signaling and Immune Regulation in Melanoma Development and Responses to Therapy. Annu Rev Pathol 12:75-102
Kawakami, Akinori; Fisher, David E (2017) The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology. Lab Invest 97:649-656
Reuben, Alexandre; Spencer, Christine N; Prieto, Peter A et al. (2017) Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma. NPJ Genom Med 2:

Showing the most recent 10 out of 89 publications