MCL-1 inhibition unmasks BCL-2 addiction in synovial sarcoma

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