An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential

Abstract

BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.

Class I HDAC inhibitors enhance YB ‐1 acetylation and oxidative stress to block sarcoma metastasis

“…Class I HDAC inhibitors are known to prevent histone deacetylation, leading to chromatin remodeling and transcriptionbased anti-neoplastic activity [41], which is the basis for their broad clinical application [51,52]. HDAC inhibitors are also reported to enhance ROS levels in melanomas [53] and other tumors [54][55][56][57] by unknown mechanisms, but other studies report modest or no effects alone [58], or even reduced ROS after longterm HDAC inhibitor treatment [59]. However, we find that MS-275 enhances ROS indirectly in sarcoma cells by non-transcriptionally inhibiting YB-1-mediated translation of NFE2L2 encoding the antioxidant master regulator, NRF2.…”

Discoidin domain receptor 2 drives melanoma drug resistance through AXL-dependent phenotype switching

“…Sequential treatment is a crucial question in clinic to abrogate the toxicity due to therapy combination or to alternate treatments (Wang et al 2018). Currently, a study demonstrated that switching from MAPK inhibitor therapy to vorinostat, is more effective in eradicating drug-resistant cells than a drug holiday (Wang et al 2018).…”

“…Sequential treatment is a crucial question in clinic to abrogate the toxicity due to therapy combination or to alternate treatments (Wang et al 2018). Currently, a study demonstrated that switching from MAPK inhibitor therapy to vorinostat, is more effective in eradicating drug-resistant cells than a drug holiday (Wang et al 2018). In this respect, we could study the effect of sequential treatment, in long term, in order to delay the apparition of resistance to vemurafenib or dasatinib (Wang et al 2018).…”

Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma

“…The acquisition of therapy resistance in cancer patients remains a major clinical challenge (Arkenau et al, 2011;Brock et al, 2009;Pritchard et al, 2012;Salgia and Kulkarni, 2018). While various genetic mutations have been reported to cause resistance (Nazarian et al, 2010;Wagle et al, 2011), recent literature also points to the importance of epigenetic modulations to drugtolerance that can precede the emergence of drug-resistant genotypes in a variety of tumor types (Bai et al, 2019;Hata et al, 2016;Hugo et al, 2015;Pisco et al, 2013;Rambow et al, 2018;Ramirez et al, 2016;Sharma et al, 2010;Wang et al, 2018). For such epigenetic processes, tumor cells adapt to the drug treatment by orchestrating master transcription factors and chromatin remodelers within a regulatory network.…”