Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia

Abstract

ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-XL as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-XL. By targeting MCL-1 and BCL-XL, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-XL alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-XL and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.

Characterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes

“…Thus, our findings may be similar to those found by Klanova et al in diffuse large B- cell lymphoma, where the combination of homoharringtonine (parent compound of omacetaxine) and ABT-199 was active 52 . This group hypothesized that the efficacy of combination treatment is due to targeting both BCL-2 and MCL-1 53 , 54 . We confirmed decreased MCL-1 levels upon treatment with omacetaxine in the MDS-L cell line (Supplementary fig.…”

Pathways and mechanisms of venetoclax resistance

“…[5] In a recent report, investigators characterized a panel of venetoclax-resistant myeloid leukemia cell lines derived through chronic exposure to venetoclax and found that acquired drug resistance was indeed driven by the up-regulation of MCL-1 and BCL-X L . [102] Interestingly, not only could the resistant AML cell lines be re-sensitized to venetoclax by targeting MCL-1 and BCL-X L , pre-emptively targeting one or both of the latter could actually delay or forestall the acquisition of venetoclax resistance. [102] These findings have obvious implications for selection of initial therapy for AML.…”

“…[102] Interestingly, not only could the resistant AML cell lines be re-sensitized to venetoclax by targeting MCL-1 and BCL-X L , pre-emptively targeting one or both of the latter could actually delay or forestall the acquisition of venetoclax resistance. [102] These findings have obvious implications for selection of initial therapy for AML.…”

Narrowing the focus: a toolkit to systematically connect oncogenic signaling pathways with cancer phenotypes

“…Among these, 39% of the pooled and 29% of the clonal populations could be resensitized to MAPK inhibition through shRNA mediated knockdown of Notch1. Similarly, we validated the finding that MCL-1 and BCL-X L up-regulation can drive resistance to the potential to be used to address many other questions in selective BCL-2 inhibitor ABT-199 (venetoclax) in acute myeloid leukemia (AML) by demonstrating the resensitization of cells with acquired resistance through knockdown or small molecule inhibition of these candidate resistance proteins [ 48 ]. Finally, we validated Ras effector pathways PI3K and MAPK as drivers of acquired resistance to JAK inhibitors in JAK2 mutant cells using a similar approach in cells with acquired JAKi resistance [ 47 ].…”