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

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.