Targets for Pik3Ca Related Overgrowth Spectrum

Pik3Ca Related Overgrowth Spectrum (PROS) is a group of disorders caused by somatic activating mutations in the PIK3CA gene, which encodes the catalytic subunit alpha of phosphatidylinositol 3-kinase (PI3K). This mutation leads to hyperactivation of the PI3K/AKT/mTOR signaling pathway, resulting in abnormal cell growth, proliferation, and survival that manifest as tissue overgrowth and vascular anomalies. A mechanistic understanding of the key molecular targets involved in this pathway—specifically PIK3CA, other PI3K catalytic subunits (PIK3CB, PIK3CD, PIK3CG), and downstream effectors such as the AKT serine/threonine kinases (AKT1, AKT2, AKT3)—is crucial for elucidating the pathogenesis of PROS. These targets collectively drive disease progression by dysregulating cellular growth and metabolic processes. This knowledge has direct implications for therapeutic development, as inhibitors targeting PI3K or AKT have demonstrated efficacy in preclinical and clinical settings for PROS and related disorders. Understanding these molecular nodes supports the identification of biomarkers for disease monitoring, informs patient stratification for targeted therapies, and guides the rational design of novel interventions. Only targets with a direct and demonstrable mechanistic relationship to PROS pathogenesis are included below.

Pi3K/Akt Pathway Core Effectors

This category encompasses the principal molecular drivers of Pik3Ca Related Overgrowth Spectrum pathogenesis: the PI3K catalytic subunits and the AKT serine/threonine kinases. Activating mutations in PIK3CA are the primary cause of PROS, leading to constitutive activation of the PI3K/AKT signaling cascade. Other class I PI3K catalytic subunits (PIK3CB, PIK3CD, PIK3CG) and the AKT kinases (AKT1, AKT2, AKT3) participate in the same pathway and may modulate disease severity or phenotype. These proteins regulate cell growth, proliferation, survival, and metabolism, and their dysregulation is central to the onset and progression of PROS. Therapeutically, this pathway is the main target of current and investigational interventions for PROS.

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)

PIK3CA encodes the p110α catalytic subunit of class IA PI3K, a lipid kinase that phosphorylates PIP2 to generate PIP3, a critical second messenger in growth factor signaling. The protein contains a p85-binding domain, C2 domain, helical domain, and a kinase domain. Regulatory mechanisms include interaction with p85 regulatory subunits and activation by receptor tyrosine kinases. Activating somatic mutations in PIK3CA are the primary pathogenic drivers in PROS, leading to constitutive PI3K activity, increased PIP3 production, and downstream AKT/mTOR pathway activation. This results in cell overgrowth and survival independent of normal growth control. Therapeutically, PI3Kα inhibitors (e.g., alpelisib) have shown efficacy in PROS, and PIK3CA mutation status serves as a biomarker for diagnosis and treatment selection. (Entrez: 5290, KEGG: 5290, UniProt: P42336)

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB)

PIK3CB encodes the p110β catalytic subunit of class IA PI3K, structurally similar to PIK3CA, with regulatory, C2, helical, and kinase domains. While not commonly mutated in PROS, PIK3CB can contribute to PI3K pathway activity and potentially compensate for PIK3CA inhibition. Its activity is modulated by interaction with regulatory p85 subunits and receptor tyrosine kinases. PIK3CB is implicated in sustaining PIP3 levels and AKT activation, particularly in contexts where PIK3CA is inhibited. Targeting PIK3CB in combination with PIK3CA may enhance therapeutic efficacy and mitigate resistance. (Entrez: 5291, KEGG: 5291, UniProt: P42338)

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD)

PIK3CD encodes the p110δ subunit, a class IA PI3K predominantly expressed in leukocytes but also present in other tissues. It shares domain architecture with other PI3K catalytic subunits. While not a primary driver in PROS, PIK3CD may modulate disease-related signaling, especially in immune or vascular components of the phenotype. Inhibition of PIK3CD (e.g., idelalisib) is therapeutically relevant in immune dysregulation but less so in PROS; however, its inclusion is justified by its potential to influence PI3K/AKT pathway output. (Entrez: 5293, KEGG: 5293, UniProt: O00329)

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG)

PIK3CG encodes the p110γ subunit of class IB PI3K, activated by G-protein-coupled receptors. It contains a Ras-binding domain, C2, helical, and kinase domains. While its role in PROS is less prominent, PIK3CG may contribute to the overall PI3K signaling milieu, particularly in the vascular and immune microenvironment. Its activity can modulate AKT phosphorylation and downstream effects. (Entrez: 5294, KEGG: 5294, UniProt: P48736)

AKT serine/threonine kinase 1 (AKT1)

AKT1 encodes a serine/threonine kinase with PH, kinase, and regulatory domains. It is activated by PIP3-mediated membrane recruitment and subsequent phosphorylation at Thr308 and Ser473. AKT1 is a principal effector of PI3K signaling, promoting cell survival, growth, and proliferation by phosphorylating numerous substrates (e.g., mTOR, FOXO, GSK3). In PROS, constitutive PI3K activity leads to persistent AKT1 activation, driving pathological overgrowth. AKT inhibitors (e.g., miransertib) are being investigated for PROS. (Entrez: 207, KEGG: 207, UniProt: P31749, Q9BWB6)

AKT serine/threonine kinase 2 (AKT2)

AKT2 shares high homology with AKT1 and contains similar PH, kinase, and regulatory domains. It is activated by the same mechanisms as AKT1 and regulates glucose metabolism, cell growth, and survival. AKT2 may contribute to tissue-specific manifestations of PROS, especially in adipose and muscle tissue. Its dysregulation amplifies the pathological effects of PI3K activation. (Entrez: 208, KEGG: 208, UniProt: P31751)

AKT serine/threonine kinase 3 (AKT3)

AKT3 is the third isoform of the AKT family, with similar structural domains as AKT1/2. It is highly expressed in the brain and may be involved in neurological manifestations of PROS. Like other AKT isoforms, it is activated by PI3K-dependent phosphorylation and promotes cellular growth and survival. (Entrez: 10000, KEGG: 10000, UniProt: Q9Y243)