Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies

Abstract

The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway plays an essential role in regulation of normal cell growth, metabolism, and survival. Somatic activating mutations in the PI3K/AKT/mTOR pathway are among the most common mutations identified in cancer, and have been shown to cause a spectrum of overgrowth syndromes including PIK3CA-Related Overgrowth Spectrum, Proteus syndrome, and brain overgrowth conditions. Clinical findings in these disorders may be isolated or multiple, including sporadic or mosaic overgrowth (adipose, skeletal, muscle, brain, vascular, or lymphatic), and skin abnormalities (including epidermal nevi, hyper-, and hypopigmented lesions), and have the potential risk of tumorigenesis. Key negative regulators of the PI3K-AKT signaling pathway include PTEN and TSC1/TSC2 and germline loss-of function mutations of these genes are established to cause PTEN Hamartoma Tumor Syndrome and Tuberous Sclerosis Complex. Mosaic forms of these conditions lead to increased activation of PI3K and mTOR at affected sites and there is phenotypic overlap between these conditions. All are associated with significant morbidity with limited options for treatment other than symptomatic therapies and surgeries. As dysregulation of the PI3K/AKT/mTOR pathway has been implicated in cancer, several small molecule inhibitors targeting different components of the PI3K/AKT/mTOR signaling pathway are under clinical investigation. The development of these therapies brings closer the prospect of targeting treatment for somatic PI3K/AKT/mTOR-related overgrowth syndromes. This review describes the clinical findings, gene function and pathogenesis of these mosaic overgrowth syndromes, and presents existing and future treatment strategies to reduce or prevent associated complications of these disorders. © 2016 Wiley Periodicals, Inc.

Keywords: PI3K/AKT/mTOR pathway; segmental overgrowth; somatic mosaicism; therapy.

Figure 1

Diagram of the PI3K/AKT/mTOR pathway and interaction with PTEN and TSC1/TSC2. Potential sites of action of inhibitors are shown. PI3K converts PIP₂ into PIP₃, which interacts with AKT at the cellular membrane where it is phosphorylated and activated. PTEN is a negative regulator of PI3K, which dephosphorylates PIP₃. AKT serves a range of cellular functions with effects on metabolism and cell survival, and through indirect activation of mTOR controls cell proliferation, protein translation, and autophagy. mTOR exists as two multi-protein complexes, mTORC1 and mTORC2. mTORC2 lies upstream of and activates AKT, whereas mTORC1 lies downstream from AKT and is activated via AKT-mediated inhibition of tuberous sclerosis complex 1 and 2 (TSC1 and2) and proline-rich Akt substrate 40 (PRAS40). The PI3K/AKT/mTOR signaling pathway exhibits cross-talk with the RAS/MAPK pathway. Abbreviations: BAD, Bcl-2 associated agonist of cell death; EGFR. Epidermal growth factor receptor; FOXO, forkhead box protein O1; IGFR, insulin-like growth factor receptor; GSK3b,glycogen synthase kinase-3; mTOR, mechanistic target of rapamycin; mTORC, mTOR complex; PDGFR, platelet-derived growth factor receptor; PDK1, protein serine/threonine kinase-3′-phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; TSC, tuberous sclerosis complex; TTF1, Thyroid transcription factor 1; SGK1, serum and glucocorticoid regulated kinase 1; VEGFR, vascular endothelial growth factor receptor; 4EBP1, 4E binding protein 1.

Figure 2

Type 1 and Type 2 segmental mosaicism with an autosomal dominant gene mutation. A. Normal embryo; B. Embryo with a germline heterozygous autosomal dominant mutation indicated with pink color throughout the body; C. Type 1 segmental mosaicism: an embryo with a post-zygotic (somatic) heterozygous mutation in a population of cells affecting a portion of developing tissues, shown in pink confined to a posterior region; D. Type 2 segmental mosaicism: an embryo like B with a germline mutation (pink shading), who in addition has a new post-zygotic mutation in a portion of cells (dark pink in posterior region), inactivating the other allele, also called loss of heterozygosity.

Figure 3

14 year old male with PROS. A. Frontal whole body view shows right facial, leg and bilateral feet hemihyperplasia (right more than left) after toe and metatarsal amputations, and left abdominal fibroadipose hyperplasia. B. Facial view shows right facial hemihyperplasia and epidermal nevus involving his right cheek and neck. C. Lymphovascular lesion involving his right arm and trunk.

Figure 4

30 year old male with Proteus syndrome. A. Cranial hyperostosis involving his right frontoparietal bones. B. Bony overgrowth with ulnar deviation of his bilateral 2^nd fingers. C. Lateral view of his right leg shows bony hemihyperplasia and vascular malformations – venous varicosities. D. Frontal view of his legs shows venous varicosities, bony overgrowth of his right leg. E. Dorsolateral view of left foot, and F. Plantar view of left foot with cerebriform connective tissue nevus (CCTN).

Figure 5

9 month old male infant with a mosaic c.5390C>T (p.Thr1977Ile) mutation in mTOR associated with megalencephaly, developmental delay, dysmorphic features, mosaic pigmentary skin changes, and polymicrogyria

Figure 6

20 year old male with PTEN Hamartoma Tumor Syndrome, who has a heterozygous p.Pro38His variant in PTEN associated with extreme macrocephaly, dysmorphic features, pigmentary skin macules, developmental delay, and intellectual disability.

Figure 7

A female with TSC diagnosed based on renal angiomyolipomas, angiofibromas, and hypomelanotic macules, has congenital overgrowth of the right thumb and forearm that may represent type 2 segmental mosaicism.