Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia

Abstract

Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift/nonsense mutations in the apoptosis effector gene BAX. In contrast, such variants were rare after genotoxic chemotherapy. BAX variants arose within either leukemic or pre-leukemic compartments, with multiple mutations observed in some patients. In vitro, AML cells with mutated BAX were competitively selected during prolonged exposure to BCL-2 antagonists. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represents a novel mechanism of resistance to BH3-mimetics and a potential barrier to longer-term efficacy of drugs targeting BCL-2 in AML.

Lymphoma cells lacking pro-apoptotic BAX are highly resistant to BH3-mimetics targeting pro-survival MCL-1 but retain sensitivity to conventional DNA-damaging drugs

“…Despite these mutations, all Bax KO Eμ-Myc lymphoma cell lines remained sensitive to killing by diverse chemotherapeutic drugs. Our findings are consistent with recent studies which found that loss of BAX could confer resistance to both venetoclax and S63845 in AMLs [42] and a panel of non-Hodgkin B cell lymphoma cell lines [43]. In addition, in this latter study, low levels of BAX mRNA were identified in samples from 3 CLL patients treated with venetoclax, and in CLL cells from another patient it was shown that BAX mutations were enriched during venetoclax treatment.…”

Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics

“…We and others have reported that MCL-1, a major resistance factor for BCL-2 inhibition, is frequently induced in VEN-resistant AML cells [ 20 – 22 ] and that co-inhibition of BCL-2 and MCL-1 is highly synergistic, both in vitro and in vivo, against various malignant cells, including AML cells and stem/progenitor cells, that have intrinsic or acquired resistance to VEN [ 18 , 23 – 28 ]. In addition, BAX mutations can confer VEN resistance to AML cells [ 29 ]. We reported that combined p53 activation and BCL-2 inhibition is synthetically lethal in TP53 -WT AML by promoting pro-apoptotic BCL-2 proteins and targeting MCL-1 [ 21 ].…”

Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia

“…genomic aberrations associated with less durable responses to venetoclax monotherapy or in combination with hypomethylating agents 20,31,[34][35][36][37] . Eftoza with or without venetoclax was also active in AML cell lines deficient in BAX, a pro-apoptotic factor that drives resistance to venetoclax-based therapies, 41 although this was less efficient than in the parental cell line. Given these observations, the development of new venetoclax-based combination regimens with novel therapeutics such as eftoza has the potential to expand treatment options for AML patients.…”