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

doi:10.1038/s41388-021-01926-y

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

Oncogene. 2021 Sep;40(38):5718-5729. doi: 10.1038/s41388-021-01926-y. Epub 2021 Jul 30.

Authors

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
² Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
³ Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA, USA.
⁴ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁵ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
⁷ Department of Hematology, UCL Cancer Institute, University College London, London, UK. [email protected].
⁸ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bridged Bicyclo Compounds, Heterocyclic / administration & dosage*
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Synergism
Everolimus / administration & dosage
Everolimus / pharmacology
Humans
Loss of Function Mutation
MTOR Inhibitors / administration & dosage*
MTOR Inhibitors / pharmacology
Melanoma / drug therapy*
Melanoma / genetics
Melanoma / pathology
Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
Neurofibromin 1 / genetics*
PTEN Phosphohydrolase / genetics*
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
Pyrimidines / administration & dosage*
Pyrimidines / pharmacology
Sirolimus / administration & dosage
Sirolimus / analogs & derivatives
Sirolimus / pharmacology
Sulfonamides / administration & dosage*
Sulfonamides / pharmacology
Thiophenes / administration & dosage*
Thiophenes / pharmacology
Xenograft Model Antitumor Assays
Zebrafish

Substances

BCL2 protein, human
Bridged Bicyclo Compounds, Heterocyclic
MCL1 protein, human
MTOR Inhibitors
Myeloid Cell Leukemia Sequence 1 Protein
NF1 protein, human
Neurofibromin 1
Proto-Oncogene Proteins c-bcl-2
Pyrimidines
S63845
Sulfonamides
Thiophenes
temsirolimus
Everolimus
PTEN Phosphohydrolase
PTEN protein, human
venetoclax
Sirolimus

Abstract

Publication types

MeSH terms

Substances

Grants and funding