Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia

Deregulation of the BCL2 gene family plays an important role in the pathogenesis of acute myeloid leukemia (AML). A BCL2 inhibitor, venetoclax, has received approval from the US Food and Drug Administration for the treatment of AML. However, upfront and acquired drug resistance ensues, in part due to the clinical and genetic heterogeneity of AML, highlighting the importance of identifying biomarkers to stratify patients onto the most effective therapies. By integrating clinical characteristics, exome and RNA sequencing, and inhibitor data from primary AML samples from patients, we determined that myelomonocytic leukemia and upregulation of BCL2A1 and CLEC7A, as well as mutations of PTPN11 and KRAS, conferred resistance to venetoclax and multiple venetoclax combinations. Venetoclax in combination with an MCL1 inhibitor, AZD5991, induced synthetic lethality and circumvented venetoclax resistance. Zhang and colleagues analyzed data from patient samples exposed to the BCL2 inhibitor venetoclax, approved for treatment of acute myeloid leukemia, identifying modes of therapy resistance and synthetic lethality with MCL1 inhibition.