PI3K/mTORC1 activation in hamartoma syndromes: therapeutic prospects

Abstract

Dysregulated activity of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin complex 1 (mTORC1) is characteristic feature of hamartoma syndromes. Hamartoma syndromes, dominantly inherited cancer predisposition disorders, affect multiple organs and are manifested by benign tumors consisting of various cell types native to the tissues in which they arise. In the past few years, three inherited hamartoma syndromes, Cowden syndrome (CS), tuberous sclerosis complex (TSC) syndrome, and Peutz-Jeghens syndrome (PJS), have all been linked to a common biochemical pathway: the hyperactivation of PI3K/mTORC1 intracellular signaling. Three tumor suppressors, PTEN (phosphatases and tensin homolog), tuberous sclerosis complex TSC1/TSC2, and LKB1, are negative regulators of PI3K/mTORC1 signaling; disease-related inactivation of these tumor suppressors results in the development of PTEN-associated hamartoma syndromes, TSC and PJS, respectively. The goal of this review is to provide a roadmap for navigating the inherently complex regulation of PI3K/mTORC1 signaling while highlighting the progress that has been made in elucidating the cellular and molecular mechanisms of hamartoma syndromes and identificating potential therapeutic targets for their treatment. Importantly, because the PI3K/mTORC1 pathway is activated in the majority of common human cancers, the identification of novel molecular target(s) for the treatment of hamartoma syndromes may have a broader translational potential, and is critically important not only for therapeutic intervention in hamartoma disorders, but also for the treatment of cancers.

Figure 1

mTORC1 signaling. mTORC1 is a master regulator of cell growth and metabolism, which mediates three major inputs from growth promoting signals such, for example, growth factors and insulin. mTORC1 directly phosphorylates and activates S6K1 and inhibit 4E-BP1, which leads to protein synthesis, cell growth and proliferation. mTORC1 is positively regulated by Akt-PRAS40 and negatively regulated by tumor suppressor complex TSC1/TSC2, which suppress activity of small GTPase Rheb. Rheb activity is positively regulated by mTCTP. TSC1/TSC2 activity is suppressed by inhibitory phosphorylation of TSC2 by PI3K-dependent Akt, ERK1/2 and ERK1/2-dependent RSK1. PI3K is activated by multiple inputs such as growth factors and insulin, which leads to recruitment of PI3K to the membrane and its binding IRS-1. Active PI3K converts phosphatidylinositol-4,5-biphosphate (PIP₂) to phosphatidylinositol-3,4,5-trisphosphate (PIP₃), which leads to PDK1-dependent phosphorylation of Akt followed by activation of mTOR in the mTORC1 complex. mTOR is part of two distinct complexes: the rapamycin-sensitive mTORC1 consisting of mTOR, raptor and adaptor protein GβL, an upstream activator of S6K1, and the rapamycin-insensitive mTORC2, consisting of mTOR, rictor and GβL. mTORC2 directly phosphorylates Akt, which is necessary for full Akt activation. In contrast, hyperactivated S6K1 inhibits IRS1-PI3K-Akt signaling pathway (the feedback loop). Tumor suppressor PTEN antagonizes PI3K-Akt signaling by specifically dephosphorylating PIP₃ to PIP₂. TSC1/TSC2 activity is positively regulated by cellular energy: increase in AMP levels due to glucose or fatty acids depravation and other stresses leads to LKB1-dependent activation of AMPK; active AMPK directly phosphorylates TSC2 and primes TSC2 for its subsequent phosphorylation by GSK3, which leads to inhibition of mTORC1, inhibition of translation, protein synthesis and cell growth. Pink or blue coloring indicate signaling molecules which are either positively or negatively, respectively, regulate cell growth and proliferation. Arrows indicate functional enhancement; flat bars indicate functional suppression.

Figure 2

Potential targeting of PI3K/mTORC1 signaling in hamartoma syndromes. Germline mutations of PTEN, LKB1, TSC1 and TSC2 genes lead to upregulation of PI3K/mTORC1 signaling and are associated with spectrum of hamartoma syndromes (Light blue boxes). Blue coloring indicate tumor suppressor proteins, negatively regulating mTORC1 signaling. Germline mutations of PTEN is associated with Cowden syndrome (CS), Lhermitte-Duclos disease (LDD), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-Like syndrome; germline mutations of LKB1 is associated with Peutz-Jeghers syndrome (PJS), TSC1 or TSC2 mutations is associated with Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM). Pink coloring indicate inhibitors of PI3K/ mTORC1 signaling pathway, which may have promising therapeutic effects for treatment of hamartoma syndromes. Rapamycin and it analogs CCI-779, RAD001 and AP23573 are to inhibit mTORC1; PI-103, SF11206 and ZSTK474 are pan-PI3K inhibitors; NVP-BEZ235 and XL765 simultaniously target mTORC1 and PI3K.