ArticleCancer science2026
MYC Addiction as a Targetable Vulnerability in Nelarabine-Resistant T-Cell Acute Lymphoblastic Leukemia.
Article in Cancer science, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Acquired resistance represents a fundamental obstacle limiting the long-term efficacy of cancer chemotherapy. In T-cell acute lymphoblastic leukemia (T-ALL), the nucleoside analog prodrug nelarabine is a critical salvage therapy for relapsed/refractory (R/R) patients; however, resistance is common and rapid, worsening prognosis. The molecular mechanisms underlying this process remain largely to be elucidated. Here, we identify the oncogene MYC as a key functional mediator driving nelarabine resistance. Through unbiased transcriptomic profiling and functional validation, we demonstrate that nelarabine-resistant T-ALL cells develop a profound addiction to a hyperactive MYC transcriptional program. Critically, MYC knockdown restores nelarabine sensitivity, causally linking MYC to the resistant phenotype. While this discovery reveals a therapeutic vulnerability, MYC itself is considered an 'undruggable' protein, making direct inhibition a formidable challenge. We therefore pursued an indirect strategy, employing BET family protein degraders to dismantle the upstream epigenetic machinery essential for MYC transcription. Consistent with a MYC-driven mechanism, treatment with ARV-771 and ARV-825 induced potent degradation of BET proteins, suppressed MYC transcription, and profoundly impaired the viability and proliferation of nelarabine-resistant cells. Importantly, this strategy showed strong therapeutic efficacy in an in vivo model of nelarabine-resistant T-ALL, significantly reducing leukemia burden and extending survival. Our work establishes the first mechanistic link between nelarabine resistance and MYC dependency, providing a compelling preclinical rationale and therapeutic strategy to overcome this challenge. Collectively, this study offers a paradigm for reversing chemotherapy resistance by exploiting acquired transcriptional addictions. Trial Registration: Registry and the Registration No. of the study/trial. Yes, approved number: IRB Approval No.: Med-Ethics [2026] IIT No. (19).
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