MYC Addiction as a Targetable Vulnerability in Nelarabine‐Resistant T‐Cell Acute Lymphoblastic Leukemia

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).