Variable Response to BCL2 Inhibition in MDS Is Enhanced across MDS Subtypes with Synergistic Combination of BCL2+MCL1 Inhibition

Myelodysplastic syndromes (MDS) are heterogeneous bone marrow failure neoplasms marked by cytopenias, reduced quality of life and predilection to transform into AML. While several treatments for AML have recently been approved, the available treatments for MDS are lacking, and adaptation of AML therapy to MDS is complicated. This is due, in part, to the heterogeneity of MDS. Despite this heterogeneity, most clonal cells in MDS have an imbalance of mitochondrial-controlled BCL2 family proteins resulting in dysregulated apoptosis. These anti- (or pro-) apoptotic proteins compete for ligand to block (or promote) apoptosis, providing an opportunity to selectively target anti-apoptotic proteins and advance therapy for MDS. Venetoclax (VEN), a newly FDA-approved therapy that specifically inhibits the anti-apoptotic protein BCL2, has yielded response rates of up to 50-70% in elderly AML including impressive responses in transformed MDS which previously failed DNMTi (DiNardo et al, 2019, Wei et al, 2019). Upregulation of the anti-apoptotic protein, induced myeloid cell leukemia-1 (MCL1), is a known resistance mechanism in AML resistant or refractory to BCL2 inhibition (Pan et al, 2014), and MCL1 increases when some MDS samples are treated with BCL2 inhibitors (Jilg et al, 2016). Therefore, strategic inhibition of BCL2 and/or MCL1 is a logical therapeutic approach in MDS. We have shown efficacy of MCL1 inhibitors in the laboratory against AML patient samples that are dependent on MCL1 protein or resistant to BCL2 inhibition, including AML cells that arose from MDS (Ramsey et al, 2018). Here, our goal was to determine the sensitivity of MDS cells to inhibition of specific anti-apoptotic proteins, elucidate the characteristic determinants of response, and investigate synergy with combined BCL2 and MCL1 inhibition.