Venous malformations: PIK3CA mutations guide new treatments

The Phosphoinositide 3-Kinase (PI3K) pathway has been extensively studied in tumors due its roles in promoting cellular growth and proliferation [1]. The most common PI3K mutations are in the PIK3CA gene encoding the p110α catalytic subunit, including the " hotspot " activating mutations E545K and H1047R that can lead to constitutive signaling of the pathway [1]. Consequently, activation of the serine/threonine kinase Akt can promote proliferative and cell growth pathways through regulation of mTOR and other intermediates [1]. In addition to driving tumorigenesis, hotspot PIK3CA mutations have also been shown to drive a wide spectrum of non-malignant over-growth disorders collectively termed the PIK3CA-Related Overgrowth Spectrum [2]. More recently, mutations in PIK3CA have been identified in venous malformations (VMs) [3], the most frequent form of vascular malformations with a frequency of about 1 in 5000 people in the general population [4]. These painful and often disfiguring lesions are characterized by endothelial cell overgrowth, loss of supporting mural cells, and a disorganized extracellular matrix resulting in dilated and distended vessels in a variety of tissues, with common occurrence in the cutaneous layer of the skin [4]. Both ubiquitous and endothelial-specific PIK3CA knockout mouse models display lethality due to angiogenic defects, directly implicating p110α in vasculogenesis [5]. Prior to the identification of PIK3CA mutations in VMs, the only known mutations were in the TEK gene that encodes the endothelial-specific Tie2 RTK. Mutations of TEK cause ligand-independent autophosphorylation of the receptor and drive signaling primarily to the PI3K and the MAPK pathways [4]. Tie2 mutations occur in about 50% of VM patients while PIK3CA mutations account for about 25% of patients with apparent mutual exclusivity [3], suggesting a functional redundancy between the two disease drivers. Two recent studies confirm the presence of PIK3CA mutations in VMs from human patients and support the notion that hyperactivation of the Tie2-PIK3CA-Akt pathway is responsible for lesion presentation [6, 7]. Castel et al used two mouse models expressing the H1047R PIK3CA mutant in either an endothelial compartment or sporadically in the body to show that aberrant PI3K signaling results in the development of VMs [6]. Similarly, Castillo et al. expressed H1047R PIK3CA in the embryonic mesoderm in a mosaic fashion and in a heterozygous state, analogous to human disease context, and observed the development of subcutaneous VMs in different body sites [7]. It is interesting to point out that in both studies, while the expression of the oncogenic …