mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

Abstract

The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1a-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

“…74 These compounds use the same inhibitory mechanism as rapamycin and are considered as potent in their antitumor capabilities. The primary difference between these compounds is their bioavailability: 11,23 temsirolimus and deforolimus are water soluble and can thus be given intravenously, whereas rapamycin and everolimus have low solubility and must be given orally. The rapalogs are primarily metabolized in the liver by the CYP450 mechanism.…”

“…Upstream activation of this pathway begins when growth factors (insulin, insulin-like growth factor, platelet-derived growth factor), mitogens, hormones, or nutrients activate PI3K. 20,22,23 PI3K is a heterodimer that consists of a catalytic subunit (p110) and a regulatory subunit (p85, p55, or p50). 22 The activated p110 catalytic subunit, encoded by the PIK3CA gene, phosphorylates phosphatidylinositol bisphosphate 4,5 on the inner leaflet of the cytoplasmic membrane to generate phosphatidylinositol triphosphate (PIP3).…”

“…11,20 Phosphorylation of 4E-BP allows assembly of the translational initiation complex with subsequent translation of proteins necessary for progression of the cell cycle past the G1 phase, such as cyclin D1. 23,27,28 NEGATIVE REGULATION OF THE mTOR-SIGNALING PATHWAY PTEN is a tumor suppressor and lipid/protein phosphatase, mapped to chromosome 10, that is commonly mutated or lost in solid tumor malignancies. 21 Furthermore, PTEN has differential functions based on its location in either the nucleus or cytoplasm.…”

Oral rapamycin reduces tumour burden and vascularization in Lkb1+/− mice

“…However, the effect of rapamycin is celltype-dependent and there is evidence to suggest that mTORC2 can be inhibited by prolonged rapamycin treatment in endothelial cells [19,22]. Hence, it is possible that the reduced angiogenesis is caused by the action of rapamycin on the proliferation or maintenance of endothelial cells [18,19]. Further experiments will be required to examine this hypothesis.…”

“…A similar level of phospho-p70S6K (pS6K, lower band; phospho-p85S6K, upper band), but an elevated level of phospho-AKT (pAKT) was detected in treated polyps, indicating the maintenance of mTORC1 but an increase in AKT signalling in these polyps available mTOR, lead to a drop in mTORC2 level in some cancer cell lines [18,19]. As mTORC2 is responsible for phosphorylating AKT at serine-473 and its activation, a decrease in mTORC2 can lead to strong inhibition of AKT signalling [19].…”