期刊
ONCOGENE
卷 40, 期 38, 页码 5718-5729出版社
SPRINGERNATURE
DOI: 10.1038/s41388-021-01926-y
关键词
-
资金
- Melanoma Research Alliance award [509233]
Loss of the NF1 tumor suppressor gene can lead to aggressive melanomas with a high risk of treatment failure. This study established a zebrafish model of NF1-mutant melanomas harboring PTEN loss and demonstrated that mTOR inhibitors and a three-drug combination can potently induce apoptosis in NF1/PTEN-deficient melanoma cells, supporting the need for early-stage clinical trials in patients.
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.
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