Researchers have implicated missense or frameshift/nonsense mutations in the BAX gene as a resistance mechanism in approximately 17% of patients with acute myeloid leukemia (AML) relapsing after treatment with the BCL-2 inhibitor venetoclax. The study, published in Blood, may affect the treatment of myeloid neoplasms.
“Acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML,” wrote the investigators, led by Donia M. Moujalled, PhD, of Monash University in Australia and colleagues.
Dr. Moujalled and colleagues reported that the study has potential implications for the long-term success of venetoclax therapy.
“Our current work highlights the importance of BAX loss-of-function defects as a potential hurdle to the long-term success of venetoclax and potentially its combination with other BH3-mimetics in the treatment of myeloid neoplasms, including AML,” they wrote.
The researchers identified BAX variants in patients with AML that included frameshift abnormalities disrupting BAX protein expression or missense variants in the COOH-terminal region impairing the pro-apoptotic function of BAX. In several cases, the progressing BAX mutant clone arose from a clonal population distinct from the original AML clone characterized at diagnosis. In contrast, BAX variants were rare in a patient cohort relapsing after conventional chemotherapy without previous venetoclax exposure.
The investigators sequenced bone marrow (BM) samples obtained from 41 patients with AML who either achieved initial remission but later relapsed (n=34) or were primary refractory (n=7) to venetoclax.
In vitro, the researchers were able to induce resistance to BCL-2 and MCL1 inhibitors (BCL-2i and MCL1i, respectively) by progressive exposure of OCI-AML3 cells to increasing doses of BCL-2i, MCL1i, or combined BCL-2i and MCL1i over a period of three months.
In terms of the mechanism, the researchers showed the defective BAX gene enhances resistance to BH3-mimetics targeting diverse BCL-2 family prosurvival proteins (including MCL1) in AML, thereby establishing a barrier to the long-term efficacy of drugs targeting BCL-2 in AML.
This was confirmed in a mouse model, in which 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 BAX mutations represent a novel mechanism of adaptive resistance to venetoclax-based therapy for patients with AML,” the researchers wrote.
Moujalled DM, Brown FC, Chua CC, et al. Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia. Blood. 2023;141(6):634-644. doi:10.1182/blood.2022016090