Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss

Shuning He, Mark W. Zimmerman, Hillary M. Layden, Alla Berezovskaya, Julia Etchin, Megan W. Martel, Grace Thurston, Chang Bin Jing, Ellen van Rooijen, Charles K. Kaufman, Scott J. Rodig, Leonard I. Zon, E. Elizabeth Patton, Marc R. Mansour, A. Thomas Look

Research output: Contribution to journalArticlepeer-review

Abstract

Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma.

Original languageEnglish
Pages (from-to)5718-5729
Number of pages12
JournalOncogene
Volume40
Issue number38
DOIs
StatePublished - Sep 23 2021

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