Abstract 5550: Understanding therapy resistance in T-cell acute lymphoblastic leukemia

Abstract The deregulation of BCL2 family proteins is a key contributor to the development of T-cell acute lymphoblastic leukemia (T-ALL). Pharmacological inhibition of these proteins, particularly through the BCL2-specific inhibitor venetoclax, has emerged as a promising therapeutic approach. However, the clinical efficacy of venetoclax is often compromised due to primary and acquired resistance mechanisms that remain incompletely understood. We employed a deep tabular learning algorithm to develop a drug sensitivity prediction model using T-ALL patient samples. Our findings revealed distinct expression profiles between drug-sensitive and drug-resistant samples. Specifically, in the context of venetoclax sensitivity and resistance phenotypes, we observed associations with several key proteins regulating the cell cycle, cytokine signaling, and mitochondrial apoptosis. Our data suggest a key link between lipid metabolism and beta-catenin signaling, which may cooperate with transcription factors regulating the transcriptional activation of key apoptosis regulatory genes. Together, our results underscore the complexity of therapy resistance and highlight the therapeutic potential of targeting multiple pathways for growth inhibition. Future research should focus on clinical trials exploring this combinatorial approach to overcome resistance and improve patient outcomes in T-ALL. Citation Format: hmad Nasimian, Kinjal Shah, Julhash U. Kazi. Understanding therapy resistance in T-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5550.