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Celebrating the 10th Anniversary

A decade of discoveries in Cancer Discovery. For the community. By the Community.

Research

Halting a Hallmark: BCL-2 Inhibition Moves from Bench to Bedside in AML

Resistance to cell death has long been appreciated as a "Hallmark of Cancer," and efforts to induce mitochondrial apoptosis in cancer cells by targeting antiapoptotic members of the BCL-2 family of proteins (e.g., BCL-2, BCL-XL, BCL-W, MCL-1) with small-molecule mimetics of proapoptotic BH3 domains were well under way by the late 2000s. The success of early clinical trials was limited by on-target, dose-limiting thrombocytopenia due to inhibition of BCL-XL in platelets, but ABT-199 (now known as venetoclax), a potent and selective inhibitor of BCL-2 without affinity for BCL-XL, was developed to circumvent that problem. In 2014, Pan, Hogdal, Letai, and colleagues found that venetoclax effectively killed AML cell lines, xenografts, and primary patient samples and showed that addiction to BCL-2 (as determined by a method called BH3 profiling that measures the rate at which BH3 peptides with affinity to specific antiapoptotic BCL-2 family proteins induce mitochondrial outer membrane permeabilization) could serve as a biomarker for venetoclax sensitivity. Inspired by these findings, Konopleva, Letai, and colleagues initiated a phase II study of venetoclax monotherapy in patients with high-risk relapsed/refractory AML and in 2016 reported an overall response rate of 19% and evidence of antileukemic activity in an additional 19% of patients. A high BCL-2/BCL-XL ratio and BCL-2 dependence as detected by BH3 profiling correlated with clinical response to venetoclax, consistent with on-target BCL-2 inhibition. Subsequent trials evaluated venetoclax in combination regimens and in newly diagnosed patients, and in 2018, the FDA granted accelerated approval to venetoclax in combination with DNA hypomethylating agents for the treatment of newly diagnosed AML in older adults or those who are not candidates for intensive induction chemotherapy.

Read 2014 article by Pan, Hogdal, Letai, and colleagues

Read 2016 article by Konopleva, Letai, and colleagues

 

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