Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia

Abstract

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, upfront resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax + azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profi le, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these fi ndings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. SIGNIFICANCE: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.

Mitochondrial determinants of response and resistance to venetoclaxpluscytarabine duplet therapy in acute myeloid leukemia

“…2B-2C). Interestingly and as opposed to previously reported treatment with VEN+AZA 49 To investigate the mechanism of cell death induced by this duplet therapy VEN+AraC, we treated AML cells exposed to VEN+AraC or single agents with the irreversible pan-caspase inhibitor Z-VAD-FMK that prevents apoptosis by blocking initiator caspases (such as caspase-2, -8, -9, and -10) and executioner/effector caspases (caspase-3, -6, and -7) 55 . We showed that Z-VAD-FMK rescued not only OCR, but also mitochondrial calcium, loss of related to calcium ion homeostasis ( Supplementary Fig.…”

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

“…Moreover, drug synergy from combining BCL2 and MCL1 inhibitors can be achieved across all subtypes and mutational profiles of MDS in this model, even in the presence of RAS family mutations that are thought to confer resistance to VEN monotherapy (eg. CBL and PTPN11 in this cohort) [14][15][16][17][18] . 38 and in vivo 11 is limited at clinically meaningful doses.…”

“…The data presented here suggest dual BCL2+MCL1 inhibition may be considered for the treatment of all MDS subtypes regardless of mutational status, even those with mutations that may be less likely to respond to VEN monotherapy (eg. TP53 or RAS family mutations) [14][15][16][17][18] MLD is multi-lineage dysplasia; EB1 is excess blasts 5-9%; EB2 is 10-19% blasts; CFU-GEMM is colony-forming unit -granulocyte, erythroid, macrophage, megakaryocyte; CFU-GM is colony-forming unit -granulocyte, macrophage; BFU-E is burst-forming unit -erythroid. n/a n/a n/a n/a n/a n/a n/a DNMTi x12 n/a DNMTi x4 DNMTi x5 DNMTi x1 DNMTi x16 DNMTi x16 n/a n/a DNMTi x3 n/a n/a n/a DNMTi x5 IMID x2…”

“…As expected, we observed an increased number of SF3B1 mutations in the lower blast count MDS patient samples (MDS-RS) 13 . RAS-family mutants, particularly PTPN11-mutated AML have previously been shown to connote resistance to VEN [14][15][16][17][18] . In this small cohort, one of 2 PTPN11 mutant MDS samples, and 2/2 CBL mutant samples were completely resistant to BCL2 inhibition (MDS033, MDS005 and MDS031, respectively).…”

Patient-tailored design of AML cell subpopulation-selective drug combinations

“…Multi-targeted therapies provide an opportunity for synergistic inhibition of multiple resistance mechanisms, including patient-specific cancer rescue pathways and phenotypic redundancy across heterogeneous cancer subclones [8][9][10][11][12][13] . However, the emergence of resistance is a dynamic process influenced by both genetic and molecular factors, together with selective pressure from the administered therapeutics; this can be seen for example in the emergence of NRAS-mutated subclones in the acquired resistance to FLT3 inhibition, 7 or intrinsic molecular and metabolic properties of monocytic subclones of patient cells resistant to venetoclax therapy 14 .…”