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MITF suppression improves the sensitivity of melanoma cells to a BRAF inhibitor.

Abstract：

:Microphthalmia-associated transcription factor (MITF) is expressed in melanomas and has a critical role in melanocyte development and transformation. Because inhibition of MITF inhibits cell growth in melanoma, MITF is a potential therapeutic target molecule. Here, we report the identification of CH6868398, which has a novel chemical structure and suppresses MITF expression at the protein level in melanoma cells. CH6868398 showed cell growth inhibition activity against MITF-dependent melanoma cells both with and without BRAF mutation and also exhibited anti-tumor efficacy in a melanoma xenograft model. Because selective BRAF inhibitors are standard therapeutics for BRAF-mutated melanoma, we investigated the effect of CH6868398 with a BRAF inhibitor, PLX4720, on cell growth inhibition. The addition of CH6868398 enhanced the cell growth inhibition activity of PLX4720 in melanoma cell lines. Furthermore, combination of CH6868398 and PLX4720 efficiently suppressed MITF protein and enhanced cleavage of Caspase3 and poly (ADP-ribose) polymerase (PARP) in melanoma cell lines. These data support the therapeutic potential of CH6868398 as an anti-melanoma agent that reduces MITF protein levels in combination with BRAF inhibitors.

journal_name

Cancer Lett

journal_title

Cancer letters

authors

Aida S,Sonobe Y,Tanimura H,Oikawa N,Yuhki M,Sakamoto H,Mizuno T

doi

10.1016/j.canlet.2017.09.008

subject

Has Abstract

pub_date

2017-11-28 00:00:00

pages

116-124

eissn

0304-3835

issn

1872-7980

pii

S0304-3835(17)30555-4

journal_volume

409

pub_type

杂志文章

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