Targeting RET–MAPK Signaling in Pediatric Solid Tumors: Molecular Biology, Therapeutic Advances, Resistance Mechanisms, and Emerging Combination Strategies

Abstract

Pediatric solid tumors are biologically heterogeneous, and a subset is driven by actionable alterations in receptor tyrosine kinases. RET (rearranged during transfection) is a clinically validated oncogenic driver in hereditary and sporadic medullary thyroid carcinoma and in RET fusion-positive thyroid cancers, while less common RET alterations have been reported across other pediatric malignancies. The development of selective RET inhibitors, particularly selpercatinib, has changed the therapeutic landscape by providing potent RET blockade with less off-target kinase inhibition than earlier multikinase inhibitors. However, durable control remains limited in some tumors by on-target resistance and, importantly, reactivation of downstream signaling through RAS–RAF–MEK–ERK or alternative receptor tyrosine kinases. This review examines RET biology, the spectrum and detection of RET alterations in pediatric solid tumors, clinical development of RET-directed therapy, pediatric pharmacologic and safety considerations, and mechanisms of therapeutic resistance. Particular emphasis is placed on the emerging rationale for combining RET inhibition with MEK or ERK inhibition as a strategy to suppress residual MAPK signaling and delay acquired resistance. Because pediatric combination evidence remains substantially less mature than adult RET-inhibitor experience, the review distinguishes established clinical evidence from preclinical hypotheses. Future progress will depend on molecularly selected trials, age-appropriate pharmacokinetic studies, longitudinal monitoring of resistance, and careful assessment of growth, skeletal, cardiovascular, hepatic, neurologic, and quality-of-life outcomes.