Unmasking BCL-2 Addiction in Synovial Sarcoma by Overcoming Low NOXA.

摘要: Synovial sarcoma (SS) is frequently diagnosed in teenagers and young adults continues to be treated with polychemotherapy variable success. The SS18-SSX gene fusion pathognomonic for the disease, high expression of anti-apoptotic BCL-2 pathologically supports diagnosis. As oncogenic itself not druggable, inhibitor-based therapies are an appealing therapeutic opportunity. Venetoclax, FDA-approved inhibitor that revolutionizing care some BCL-2-expressing hematological cancers, affords intriguing possibility treat SS. In addition, there now dozens venetoclax-based combination clinical trials attributing limited toxicity venetoclax. However, preclinical studies venetoclax SS have demonstrated unexpected ineffectiveness. this study, we analyzed response underlying family biology effort understand treatment failure find a strategy sensitize We found remarkably depressed levels endogenous MCL-1 inhibitor, NOXA, compared other sarcomas. Expressing NOXA led sensitization venetoclax, as did addition BH3 mimetic, S63845. Importantly, venetoclax/S63845 induced tumor regressions patient-derived xenograft (PDX) models. very close analog S63845 (S64315) AML (NCT03672695), mimetics should considered patients new therapy.