MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells.

Cell Death & Disease
Nabanita MukherjeeYiqun G Shellman

Abstract

Current treatment for patients with metastatic melanoma include molecular-targeted therapies and immune checkpoint inhibitors. However, a subset of melanomas are difficult-to-treat. These melanomas include those without the genetic markers for targeted therapy, non-responsive to immunotherapy, and those who have relapsed or exhausted their therapeutic options. Therefore, it is necessary to understand and explore other biological processes that may provide new therapeutic approaches. One of most appealing is targeting the apoptotic/anti-apoptotic system that is effective against leukemia. We used genetic knockdown and pharmacologic approaches of BH3 mimetics to target anti-apoptotic BCL2 family members and identified MCL1 and BCLXL as crucial pro-survival members in melanoma. We then examined the effects of combining BH3 mimetics to target MCL1 and BCLXL in vitro and in vivo. These include clinical-trial-ready compounds such as ABT-263 (Navitoclax) and S63845/S64315 (MIK655). We used cell lines derived from patients with difficult-to-treat melanomas. In vitro, the combined inhibition of MCL1 and BCLXL resulted in significantly effective cell killing compared to single-agent treatment (p < 0.05) in multiple assays, including sphe...Continue Reading

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Citations

Jan 14, 2021·Cellular and Molecular Life Sciences : CMLS·Camilla S A Davan-WettonTrinidad Montero-Melendez
Nov 17, 2020·GeroScience·Melod MehdipourIrina M Conboy
Feb 6, 2021·Drug Discovery Today·Daniela Trisciuoglio, Donatella Del Bufalo
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Sep 14, 2021·Biochemical Society Transactions·Erinna F Lee, W Douglas Fairlie
Sep 29, 2021·Biochemical Society Transactions·W Douglas Fairlie, Erinna F Lee

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Datasets Mentioned

BETA
ABT-263

Methods Mentioned

BETA
xenografts
xenograft
Assay

Clinical Trials Mentioned

NCT03672695
NCT01989585

Software Mentioned

GraphPad Prism
Elements BR - software
IncuCyte
NIS

Related Concepts

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