MAPK-driven MYC/p21 axis controls senescence bypass and BCL-XL dependence in vincristine-resistant rhabdomyosarcoma

Abstract

Summary Therapy resistance remains the primary cause of treatment failure in rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, yet underlying mechanisms are poorly understood. Using vincristine-resistant fusion-negative RMS models, RNA sequencing, genetic perturbations, and a syngeneic zebrafish tumor model, we demonstrate that resistance is driven by enhanced MAPK signaling, validated in post-chemotherapy patient specimens. MEK inhibition induced senescence through an MYC-p21 axis; MYC represses CDKN1A transcription, and its overexpression bypasses senescence. Resistant cells exhibited BCL-XL dependence, and combined MEK/BCL-XL inhibition eradicated resistant tumors in vitro and in vivo. These findings reveal that enhanced MAPK signaling and MYC-mediated senescence bypass are candidate resistance-associated mechanisms in fusion-negative RMS with implications across cancer types, and identify targetable vulnerabilities (MEK and BCL-XL), providing preclinical rationale for treatment-refractory RMS.