Advances in the Targeted Therapy for PIK3CA-Related Overgrowth Spectrum (PROS): From Molecular Mechanisms to Clinical...

The PIK3CA-related overgrowth spectrum (PROS) encompasses a group of rare, somatic disorders caused by somatic activating mutations in PIK3CA, resulting in a dysregulated PI3K/AKT/mTOR pathway and consequent segmental tissue overgrowth and vascular malformations affecting multiple tissue types. This review synthesizes advances in targeted therapy for PROS, focusing on molecular rationale, clinical evidence, limitations, and future perspectives of targeting the PI3K/AKT/mTOR pathway. Overall, the selective PI3Kα inhibitor alpelisib has shown reductions in lesion burden and improvements in functional outcomes, with a generally manageable safety profile. Other agents, including taselisib and miransertib, have shown limited clinical benefits, and their further development has been constrained by safety concerns and insufficient efficacy. Although mTOR inhibitors, such as sirolimus, have shown partial efficacy in symptom control, durable responses remain uncommon, and recurrence after treatment discontinuation has been observed. Long-term safety, particularly in pediatric populations, remains to be fully established. In conclusion, targeted therapies, particularly alpelisib, represent a significant advancement in the management of PROS, although optimization of patient selection, long-term risk assessment, and strategies to minimize recurrence remain important unmet needs.