Targeting RAS/MAPK Signaling in Pediatric Gastrointestinal Malignancies: Current Challenges and Future Directions

Pediatric gastrointestinal (GI) cancers are rare malignancies that differ fundamentally from their adult counterparts in molecular drivers, histology, and clinical behavior. While adult GI cancers are frequently driven by recurrent oncogenic mutations, pediatric tumors often exhibit pathway-level dysregulation involving developmental signaling networks. Among these, the RAS/MAPK pathway emerges as a central convergent axis integrating growth factor signaling, developmental programs, inflammatory cues, and post-translational regulatory mechanisms. Increasing evidence suggests that aberrant phosphorylation dynamics result from imbalanced kinase activation and phosphatase-mediated signal attenuation which contribute to sustained MAPK signaling in pediatric GI malignancies, even in the absence of canonical RAS or RAF mutations. This review synthesizes current knowledge on RAS/MAPK signaling in pediatric GI cancers, emphasizing the role of kinase–phosphatase imbalance, signal duration, and regulatory failure in shaping oncogenic outcomes. We highlight how altered phosphorylation control may influence tumor differentiation, therapeutic responsiveness, and resistance mechanisms, and discuss emerging opportunities for targeting signaling dynamics rather than single genetic lesions. This signaling-centric framework provides a biologically grounded rationale for functional biomarker-driven precision therapy in pediatric GI malignancies.