Histone Modifications, Modifiers and Readers in Melanoma Resistance to Targeted and Immune Therapy

Abstract

The treatment of melanoma has been revolutionized by new therapies targeting MAPK signaling or the immune system. Unfortunately these therapies are hindered by either primary resistance or the development of acquired resistance. Resistance mechanisms involving somatic mutations in genes associated with resistance have been identified in some cases of melanoma, however, the cause of resistance remains largely unexplained in other cases. The importance of epigenetic factors targeting histones and histone modifiers in driving the behavior of melanoma is only starting to be unraveled and provides significant opportunity to combat the problems of therapy resistance. There is also an increasing ability to target these epigenetic changes with new drugs that inhibit these modifications to either prevent or overcome resistance to both MAPK inhibitors and immunotherapy. This review focuses on changes in histones, histone reader proteins and histone positioning, which can mediate resistance to new therapeutics and that can be targeted for future therapies.

Keywords: BET; BRAF; EZH2; HDAC; MEK; PD-1; PD-L1; PRC2; RAF; bromodomain; chromatin modifiers; histones; immunotherapy; methyltransferase; resistance.

Figure 1

Mechanisms conferring resistance to MAPK inhibitors restore survival signaling by decreasing pro-apoptotic proteins and increasing anti-apoptotic signals. A variety of epigenetic modulators can push the balance back to signaling that favors cell death.

Figure 2

Melanoma cells develop resistance to MAPK inhibitors by mutating (mut) or altering expression of a number of proteins which reactivate MAPK signaling and/or activate alternative survival pathways such as the PI3K pathway. Some alterations known to drive resistance are shown in blue. Targeting epigenetic regulators may be able to overcome these resistance mechanisms by targeting the resistance mechanism directly or downstream signaling.

Figure 3

Melanoma cells evade immune attack using a number of mechanisms. Inhibitors of CTLA-4 and PD-1/PD-L1 have shown success in the clinic but some melanoma tumors are resistant. Epigenetic modulators can stimulate immune killing of melanoma by modulating antigen presentation, receptor expression and cytokine production in both melanoma and immune cells. However the effect of epigenetic modulators on immune cell viability and function is not fully understood and the effects differ for different immune cells. This makes the net result of many epigenetic modulators on anti-tumor immune function difficult to predict.