Pathomechanisms of Dermatologic Adverse Effects of Targeted Therapies in Pediatric Solid Tumors: A Narrative Review.
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PURPOSE OF REVIEW: Targeted anticancer therapies have transformed the treatment of pediatric solid tumors but are associated with a distinct spectrum of dermatologic adverse effects that may impair quality of life and compromise treatment adherence. This review summarizes the molecular and cellular mechanisms underlying these toxicities and integrates current mechanistic evidence with their clinical manifestations, prevention, and management. RECENT FINDINGS: Recent mechanistic and clinical evidence indicates that targeted therapy-related cutaneous toxicities arise from pathway-specific disruption of epidermal, vascular, and immune homeostasis. Major mechanisms include paradoxical MAPK activation during BRAF inhibition; impaired keratinocyte proliferation, differentiation, and barrier function during MEK, EGFR, and mTOR inhibition; endothelial and epidermal injury associated with VEGFR-targeting multikinase inhibitors; and loss of immune tolerance during immune checkpoint blockade. These mechanisms contribute to characteristic phenotypes including papulopustular eruptions, xerosis, paronychia, hand-foot skin reaction, pigmentary alterations, and immune-mediated dermatoses. Pediatric-specific mechanistic and prospective dermatologic data remain limited, and evidence for several newer targeted agents is largely extrapolated from adult studies. Dermatologic toxicities of targeted therapies reflect predictable perturbations of signaling pathways that are also essential for normal skin homeostasis. Understanding these pathomechanisms may facilitate early recognition, mechanism-based prevention and treatment, and preservation of anticancer therapy. Pediatric-specific prospective studies and standardized dermatologic outcome reporting are needed.