Genomic Subtype Influences BH3 Mimetic Drug Sensitivity and Synergy with Cytotoxic Chemotherapeutics in T-cell Acute Lymphoblastic Leukemia

PURPOSE: BH3 mimetics targeting anti-apoptotic BCL2 family proteins are promising therapeutics for T-cell acute lymphoblastic leukemia (T-ALL). However, their activity across genomic subtypes of this cancer and interactions with other anti-leukemic agents remain incompletely defined. EXPERIMENTAL DESIGN: We evaluated the ex vivo sensitivity of BCL2/BCL-XL dual, BCL2-, BCL-XL-, and MCL1-selective inhibitors across 58 T-ALL patient-derived xenografts representing diverse molecular subtypes. The BCL2-BCL-XL dual inhibitor AZD4320 was further assessed in combination with selected anti-leukemic agents. Drug responses were quantified by dose-dependent induction of apoptosis and integrated with genomic and functional analyses. RESULTS: AZD4320 demonstrated subtype-specific cytotoxicity, with increased sensitivity in ETP-like T-ALL and resistance in TAL1 αβ-like T-ALL. Gene network analysis revealed subtype-dependent activation of distinct BCL2 family proteins, with AZD4320 response associated with BCL2 and MCL1 activity. Drug-drug interaction analysis using the MuSyC algorithm showed that AZD4320 synergized by potency-rather than maximal efficacy-with asparaginase and dasatinib, particularly broad interaction with asparaginase across subtypes. In vivo, AZD4320-asparaginase combination therapy conferred survival benefit. Mechanistically, asparaginase-induced asparagine depletion promoted mitochondrial dysfunction, potentiating AZD4320-mediated cytotoxicity. CONCLUSIONS: These findings highlight genomic context in shaping BH3 mimetic responses and point to rational combination of this class of drugs with anti-leukemic agents such as asparaginase.