The mTOR pathway in obesity driven gastrointestinal cancers: Potential targets and clinical trials

The mechanistic target of rapamycin (mTOR) is a crucial point of convergence between growth factor signalling, metabolism, nutrient status and cellular proliferation. The mTOR pathway is heavily implicated in the progression of many cancers and is emerging as an important driver of gastrointestinal (GI) malignancies. Due to its central role in adapting metabolism to environmental conditions, mTOR signalling is also believed to be critical in the development of obesity. Recent research has delineated that excessive nutrient intake can promote signalling through the mTOR pathway and possibly evoke changes to cellular metabolism that could accelerate obesity related cancers. Acting through its two effector complexes mTORC1 and mTORC2, mTOR dictates the transcription of genes important in glycolysis, lipogenesis, protein translation and synthesis and has recently been defined as a central mediator of the Warburg effect in cancer cells. Activation of the mTOR pathway is involved in both the pathogenesis of GI malignancies and development of resistance to conventional chemotherapy and radiotherapy. The use of mTOR inhibitors is a promising therapeutic option in many GI malignancies, with greatest clinical efficacy seen in combination regimens. Recent research has also provided insight into crosstalk between mTOR and other pathways which could potentially expand the list of therapeutic targets in the mTOR pathway. Here we review the available strategies for targeting the mTOR pathway in GI cancers. We discuss current clinical trials of both established and novel mTOR inhibitors, with particular focus on combinations of these drugs with conventional chemotherapy, radiotherapy and targeted therapies. (C) 2015 The Authors. Published by Elsevier B.V.