Disrupting resistance: novel therapeutic approaches to combat multidrug resistance in fusion-negative rhabdomyosarcoma

Rhabdomyosarcomas (RMS) are aggressive pediatric soft tissue tumors. The fusion-negative subtype (FN-RMS) is characterized by RAS pathway mutations and genomic instability. While standard chemotherapies -vincristine, actinomycin D, and alkylating agents -are effective against localized disease, multidrug resistance (MDR) often leads to treatment failure in relapsed and metastatic RMS. Key drivers of MDR in FN-RMS include dysregulated RAS/PI3K signaling, enhanced DNA repair, evasion of apoptosis, and alterations in drug transport and metabolism. Preclinically, vertical inhibition of the RAS/MAPK and PI3K/AKT/mTOR pathways shows promise but is limited by toxicity and compensatory feedback. Combination strategies targeting MEK, IGF1R, and PI3K, as well as epigenetic regulators and metabolic pathways, demonstrate synergistic effects. BH3 mimetics can restore apoptotic sensitivity, especially in FBW7-deficient tumors. Radiotherapy resistance is mediated through the DNA-PK–mTORC2–AKT axis, while drug transporters such as ABCB1 and SLC7A11, along with age-dependent CYP enzymeexpression, affect drug bioavailability. Targeting these convergent mechanisms offers a promising therapeutic strategy to overcome resistance in FN-RMS.