Drugging the Epigenome: Overcoming Resistance to Targeted and Immunotherapies in Melanoma

Reversing vemurafenib‐resistance in primary melanoma cells by combined romidepsin and type I IFN treatment through blocking of tumorigenic signals and induction of immunogenic effects

“…43,44 Of interest, epigenetic driver mutations may shape melanoma immune phenotype by affecting IFN responsiveness and favoring immune evasion thus HDACi showed the ability in promoting the shift to proinflammatory TME, 45,46 and several trials are evaluating the effects of HDAC inhibition in melanoma. 3 In our study, we show that the HDAC class I-selective agent romidepsin, inhibited to the same degree the proliferation of MITF high cells, whereas exerted slightly weaker antiproliferative effects against AXL high cells. Noteworthy, the combination of romidepsin with the immunomodulatory agent IFN resulted in a cooperative antiproliferative effect in all tested MM cells.…”

“…MITF low ‐driven melanoma phenotype‐switch is associated with activated histone modifications whereas AXL expression under HDAC control is reversed in glioma by combined treatment of AXL and HDAC inhibitors showing potent antitumor effects 43,44 . Of interest, epigenetic driver mutations may shape melanoma immune phenotype by affecting IFN responsiveness and favoring immune evasion thus HDACi showed the ability in promoting the shift to proinflammatory TME, 45,46 and several trials are evaluating the effects of HDAC inhibition in melanoma 3 . In our study, we show that the HDAC class I‐selective agent romidepsin, inhibited to the same degree the proliferation of MITF high cells, whereas exerted slightly weaker antiproliferative effects against AXL high cells.…”

“…Drugs blocking the MAPK cascade have drastically improved the survival rate of a significant proportion of patients, but this success is hampered by emergence of drug resistance involving MAPK signaling reactivation or other proliferative and survival pathways, such as PI3K‐AKT‐mTOR 2 . Acquired drug resistance is also driven by other elements, such as epigenetic events supporting the prevalence of slow‐cycling cancer cells 3 . Finally, BRAFi resistance is also influenced by TME inflammation, sustaining melanoma phenotypic switch and functional alterations of immune populations 4,5 …”

“…2 Acquired drug resistance is also driven by other elements, such as epigenetic events supporting the prevalence of slow-cycling cancer cells. 3 Finally, BRAFi resistance is also influenced by TME inflammation, sustaining melanoma phenotypic switch and functional alterations of immune populations. 4,5 A master regulator of melanoma cell plasticity is MITF, which regulates the expression of genes driving the melanoma phenotypic switch.…”

Modulation of A375 human melanoma cell proliferation and apoptosis by nitric oxide

“…NO • may also be pivotal during skin cancer therapy by way of mediating treatment resistance to cisplatin treatment in melanoma cells in vitro (Chen et al, 2021;Drača et al, 2021;Mazurek and Rola, 2021). Strong clinical and experimental evidence shows a correlation between the production of NO • by tumor cells and reduced survival of patients with advanced melanoma (Dind et al, 2021;, Obrador et al, 2021 as well as poor response to chemotherapy and radiation therapy (Skudalski et al, 2022;Hanly et al, 2022). However, the molecular mechanisms through which NO • induces apoptosis in human melanoma cells or protects tumors have not been fully defined.…”