abt-199 and Melanoma

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.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Everolimus; Humans; Loss of Function Mutation; Melanoma; MTOR Inhibitors; Myeloid Cell Leukemia Sequence 1 Protein; Neurofibromin 1; Proto-Oncogene Proteins c-bcl-2; PTEN Phosphohydrolase; Pyrimidines; Sirolimus; Sulfonamides; Thiophenes; Xenograft Model Antitumor Assays; Zebrafish

Topics: Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Gene Expression Profiling; Humans; Melanoma; Molecular Mimicry; Protein Interaction Domains and Motifs; Sulfonamides