RT Journal Article
SR Electronic
T1 The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.30.320580
DO 10.1101/2020.09.30.320580
A1 Muzhou Wu
A1 Ailish Hanly
A1 Frederick Gibson
A1 Kevin Kuang
A1 Jay Kalin
A1 Sarah Nocco
A1 Marianne Collard
A1 Matthew Cole
A1 Amy Xiao
A1 Filisia Agus
A1 Adam Labadorf
A1 Philip A Cole
A1 Rhoda M. Alani
YR 2020
UL http://biorxiv.org/content/early/2020/10/02/2020.09.30.320580.abstract
AB Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events1,2. Although the epigenetic landscape has been shown to be altered in therapy-resistant melanomas and other cancers3,4, a specific targetable epigenetic mechanism regulating treatment resistance has not been validated to date. Here we evaluate the CoREST repressor complex and the novel inhibitor, corin5, within the context of melanoma phenotype plasticity and therapeutic resistance in order to define epigenetic mechanisms underlying these processes. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. We further demonstrate that treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin leads to resensitization of tumor cells to BRAFi. Among the transcriptional targets of CoREST in melanoma are the dual-specificity phosphatases (DUSPs). DUSP1 is shown to be consistently downregulated in BRAFi-resistant melanomas which can be reversed by corin treatment, thereby leading to downstream inhibition of p38 MAPK activity and resensitization of resistant cells to targeted BRAFi therapies. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAF-mutant melanomas who have acquired BRAFi-resistance.Competing Interest StatementJay Kalin and Philip Cole are coinventors on the below application which covers corin. The US patent is pending. U.S. Patent Application No. 15/124,208 Filed: 07-Sep-2016. Based on PCT/US2015/019467 Filed: 09-Mar-2015. Entitled: INHIBITORS OF HISTONE LYSINE SPECIFIC DEMETHYLASE (LSD1) AND HISTONE DEACETYLASES (HDACS)