Venetoclax-resistant AML cell models as a platform for exploring new generation drug for BCL2 inhibitor resistance

BCL2 is a key regulatory protein in the apoptotic pathway. Venetoclax (ABT-199), an orally bioavailable and highly selective BCL-2 inhibitor, has demonstrated promising efficacy in acute myeloid leukemia (AML) when used in combination with hypomethylating agents (HMA), leading to high remission rates and significantly prolonged overall survival. However, a considerable number of patients developed resistance or experienced relapse, highlighting the need for new strategies to overcome acquired venetoclax resistance. To investigate this issue, we established venetoclax-resistant models in three AML cell lines (RS4;11, MOLM-13, and MV 4-11) through prolonged exposure to progressively increasing concentrations of venetoclax (ranging from 1 nM to 500 nM). The resulting resistant cells exhibited a marked reduction in venetoclax sensitivity, with resistance levels exceeding 160-fold compared to their parental counterparts. These models serve as a valuable platform for evaluating novel BCL-2 inhibitors, combination treatment regimens, and other targeted agents. Moreover, they provide a crucial resource for elucidating the underlying mechanisms of venetoclax resistance.