MCL1 dependence across MDS subtypes and dual inhibition of MCL1 and BCL2 in MISTRG6 mice

Abstract

Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and clinical complexity. Dysregulation of apoptosis is observed across MDS subtypes regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein B-cell lymphoma-2 (BCL2), has yielded impressive responses in older patients with acute myeloid leukemia (AML). BCL2 family antiapoptotic proteins BCL-X L and induced myeloid cell leukemia 1 (MCL1) are implicated in leukemia survival, and upregulation of MCL1 is seen in VEN-resistant AML and MDS. Here, we determined the in vitro sensitivity of MDS patient samples to selective inhibitors of BCL2, BCL-X L and MCL1. While VEN response positively correlated with increasing blast counts, all MDS subtypes responded to the MCL1 inhibitor, S63845. Treatment with combined VEN+S63845 was synergistic in all MDS subtypes and reduced MDS engraftment in MISTRG6 mice supporting the pursuit of clinical trials with combined BCL2+MCL1 inhibition in MDS.

Emerging treatments for myelodysplastic syndromes: Biological rationales and clinical translation

“…Venetoclax (ABT199) is a highly selective BCL2 inhibitor that promotes the oligomerization of BAX and BAK, thus inducing apoptosis 62 , 63 , 64 ( Figure 3 ). Since its approval by the US Food and Drug Administration (FDA) in 2019, venetoclax has substantially improved the treatment outcomes of patients with AML.…”