Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases

Abstract

Mammalian target of rapamycin (mTOR) is the core component of two complexes, mTORC1 and mTORC2. mTORC1 is inhibited by rapamycin and analogues. mTORC2 is impeded only in some cell types by prolonged exposure to these compounds. mTOR activation is linked to tubular cell proliferation in animal models and human autosomal dominant polycystic kidney disease (ADPKD). mTOR inhibitors impede cell proliferation and cyst growth in polycystic kidney disease (PKD) models. After renal transplantation, two small retrospective studies suggested that mTOR was more effective than calcineurin inhibitor-based immunosuppression in limiting kidney and/or liver enlargement. By inhibiting vascular remodeling, angiogenesis, and fibrogenesis, mTOR inhibitors may attenuate nephroangiosclerosis, cyst growth, and interstitial fibrosis. Thus, they may benefit ADPKD at multiple levels. However, mTOR inhibition is not without risks and side effects, mostly dose-dependent. Under certain conditions, mTOR inhibition interferes with adaptive increases in renal proliferation necessary for recovery from injury. They restrict Akt activation, nitric oxide synthesis, and endothelial cell survival (downstream from mTORC2) and potentially increase the risk for glomerular and peritubular capillary loss, vasospasm, and hypertension. They impair podocyte integrity pathways and may predispose to glomerular injury. Administration of mTOR inhibitors is discontinued because of side effects in up to 40% of transplant recipients. Currently, treatment with mTOR inhibitors should not be recommended to treat ADPKD. Results of ongoing studies must be awaited and patients informed accordingly. If effective, lower dosages than those used to prevent rejection would minimize side effects. Combination therapy with other effective drugs could improve tolerability and results.

Figure 1

Schematic overview of the mTOR complexes, mTORC1 and mTORC2, and of the feedback loop. (A) The rapamycin-sensitive mTORC1 comprises, in addition to the mTOR kinase, raptor, GβL, PRAS40, and DEPTOR. (B) mTORC2 contains Rictor, GβL, Protor, Sin, and DEPTOR. (C) mTORC1 regulates translation, cell size, and the cell cycle, as well as autophagy and cellular metabolism. mTORC2 regulates the cellular cytoskeleton. In addition, mTORC2 is the kinase responsible for phosphorylation of Akt in Ser473. Activation of mTORC1 results in regulation of a negative feedback loop through which S6K inhibits the insulin receptor signaling by phosphorylating and inducing degradation of the adaptor IRS. As a consequence, activation of mTORC1 downregulates PI3k/Akt and the ERKs, whereas inhibition of mTORC1 upregulates both cascades.

Figure 2

Overview of the cascades converging on regulation of the TSC2 gene product tuberin. Downstream of the tyrosine kinase receptor (TKR) signaling, Akt, ERK, and p90RSK can all phosphorylate different residues of TSC2, resulting in inhibition of its GAP activity toward Rheb (right diagram). As a result, activation of TKRs results in activation of the mTORC1 cascade. Amino acids can also activate mTORC1 downstream of the TSC1/TSC2 complex by acting directly on mTORC1. In contrast, REDD1, AMPK, and GSK3β act as energy or hypoxia sensors and are able to potently inhibit the mTORC1 cascade by enhancing the TSC1/TSC2 activity toward Rheb (left diagram). Wnts can activate the mTORC1 complex by inhibiting GSK3β.

Figure 3

Multiple signaling (AMPK, Ras/ERK, PIK3) pathways converge at the TSC1-TSC2 complex to regulate the rapamycin-sensitive mTORC1 activity, protein synthesis, and cell growth. Mutations of at least seven (blue) disease genes associated with Mendelian hamartoma syndromes have been linked to mTORC1 activation (see text for more details), providing a rationale for the potential therapeutic use of mTOR inhibitors in these disorders. 4EBP1, initiation factor 4E binding protein; FNIP1, folliculin-interacting protein 1; NF1, neurofibromin 1; PTEN, phosphatase and tensin homolog; RSK, p90 S6K 1; STK11, serine/threonine kinase 11 (also known as LKB1); TSC1, hamartin; TSC2, tuberin.