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 amongst 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.

Molecular diagnosis of somatic overgrowth conditions: A single‐center experience

“…Molecular diagnosis of a somatic overgrowth condition can help guide patient management, aid in family planning, and may offer therapeutic opportunities. For individuals with a P/LP variant in the PIK3CA‐AKT‐mTOR pathway, mTOR inhibitors and small molecular inhibitors targeting AKT or PIK3CA, initially developed for oncological purposes, are now showing promise in off‐label trials and pre‐clinical models for management of somatic overgrowth conditions (e.g., sirolimus: NCT02428296; ARQ 092: NCT03094832) (Akgumus et al, ; Chang et al, ; Keppler‐Noreuil et al, ).…”

“…A heterogeneous group of overgrowth conditions are caused by post‐zygotic pathogenic variants, resulting in segmental mosaicism and give rise to neural, cutaneous and/or lipomatous overgrowth (Akgumus, Chang, & Li, ; Chang et al, ; Keppler‐Noreuil, Parker, Parker, Darling, & Martinez‐Agosto, ). Typically, these variants arise in growth‐promoting pathways, most commonly the PI3K‐AKT‐MTOR pathway, leading to cellular proliferation and enlargement of tissues arising from the affected cellular lineage.…”

RAS Proteins and Their Regulators in Human Disease

“…Comparison of RASopathies with germline diseases of the PI3K pathway, such as PIK3CA-related overgrowth spectrum, Proteus syndrome, Cowden syndrome, and tuberous sclerosis complex (Keppler-Noreuil et al, 2016) is also of great interest, because of the close and complicated relationship between these major signaling pathways. Some of their phenotypes overlap.…”

mTORC1 signaling and the metabolic control of cell growth

“…These diseases include those characterized by uncontrolled growth, including somatic overgrowth disorders (e.g. macrocephaly, proteus syndrome), tumor syndromes (e.g., Cowden syndrome, TSC, lymphangioleiomyomatosis), and the majority of sporadic cancers [105,106]. These settings are likely to offer the clearest insights into the biological consequences of aberrant uncoupling of normal control mechanisms upstream of mTORC1 from the pro-growth metabolic program that mTORC1 induces.…”