Differentiated In Vitro Efficacy of BYL719, ARQ092, and Rapamycin on Fibroblasts Isolated From a Chinese PIK3CA-Related Overgrowth Spectrum Individual With a Novel Variant.

Postzygotic mutations of the PIK3CA gene constitutively activate the PI3K/AKT/mTOR pathway in patients with PIK3CA-related overgrowth spectrum (PROS), causing congenital mosaic tissue overgrowth. We established primary fibroblast cells from a patient with a novel somatic frameshift mutation (c.3190_3191insA, [p.H1065fs]) in PIK3CA, in which PI3K/AKT/mTOR signaling is activated compared to control fibroblasts. We assessed the therapeutic effects of three compounds (BYL719, ARQ092, and rapamycin) on the PI3K/AKT/mTOR signaling pathway and cell growth. Notably, BYL719 is more effective at inhibiting the overactivation of all key signaling molecules in the pathway at lower concentrations in patient-derived fibroblasts, while showing no significant effect on control fibroblasts. The insertion frameshift mutation is not located within the five domains, but it is a gain-of-function PIK3CA mutation contributing to PROS development. The results further confirmed the obvious advantages of the compound in targeted therapy for PROS patients.