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

<jats:p>&lt;div&gt;AbstractPurpose:&lt;p&gt;BH3 mimetics targeting antiapoptotic 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 antileukemic agents remain incompletely defined.&lt;/p&gt;Experimental Design:&lt;p&gt;We evaluated the ex vivo sensitivity of BCL2/BCL-XL dual, BCL2-, BCL-XL-, and MCL1-selective inhibitors across 58 xenografts derived from T-ALL, representing diverse molecular subtypes. The BCL2/BCL-XL dual inhibitor AZD4320 was further assessed in combination with selected antileukemic agents. Drug responses were quantified by dose-dependent induction of apoptosis and integrated with genomic and functional analyses.&lt;/p&gt;Results:&lt;p&gt;AZD4320 demonstrated subtype-specific cytotoxicity, with increased sensitivity in early T-cell precursor (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 Multi-dimensional Synergy of Combinations 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 a survival benefit. Mechanistically, asparaginase-induced asparagine depletion promoted mitochondrial dysfunction, potentiating AZD4320-mediated cytotoxicity.&lt;/p&gt;Conclusions:&lt;p&gt;These findings highlight the genomic context in shaping BH3 mimetic responses and point to the rational combination of this class of drugs with antileukemic agents such as asparaginase.&lt;/p&gt;&lt;/div&gt;</jats:p>