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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Acquired resistance limits chemotherapy efficacy in T-cell acute lymphoblastic leukemia (T-ALL).
• Nelarabine is a key salvage therapy for relapsed/refractory (R/R) T-ALL, but resistance is common.
• Molecular mechanisms of nelarabine resistance are not well understood.

Purpose of the Study:

• To elucidate the molecular mechanisms driving nelarabine resistance in T-ALL.
• To identify novel therapeutic strategies to overcome nelarabine resistance.

Main Methods:

• Unbiased transcriptomic profiling of nelarabine-resistant T-ALL cells.
• Functional validation including MYC knockdown experiments.
• Treatment with BET family protein degraders (ARV-771, ARV-825) in vitro and in vivo.

Main Results:

• Nelarabine-resistant T-ALL cells exhibit addiction to a hyperactive MYC transcriptional program.
• MYC knockdown restored sensitivity to nelarabine.
• BET protein degraders suppressed MYC transcription and impaired resistant cell viability.
• Therapeutic efficacy was demonstrated in an in vivo model of nelarabine-resistant T-ALL.

Conclusions:

• MYC is a key mediator of nelarabine resistance in T-ALL.
• Targeting MYC transcription via BET protein degraders is a viable strategy to overcome nelarabine resistance.
• This approach offers a new paradigm for reversing chemotherapy resistance by exploiting transcriptional dependencies.