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

Abstract

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.

Keywords: Clinical trials; Gastrointestinal cancers; Obesity; mTOR.

Fig. 1

Schematic representation of the mTOR pathway, it's classical upstream inputs and downstream targets. mTOR exists as two separate signalling complexes which are structurally distinct. mTOR complex 1, which is defined by raptor, receives signalling inputs from amino acids, ATP, insulin, growth factors and hormones, which all culminate in the initiation of multiple downstream signalling pathways. mTORC1 phosphorylates a limited number of known substrates, the principle ones being S6K1, 4EBP1, SREBP and GRB10. Activation of these mTORC1 targets culminates in the up regulation of anabolic processes and the down regulation of catabolic processes and mediates a negative feedback loop towards PI3K via S6K1. mTORC2, while not as throughly studied as mTORC1, is defined by raptor and is activated by PI3K signalling and acts downstream on Akt.

Fig. 2

Summary of the emerging role of the mTOR pathway in obesity related gastrointestinal malignancies. While the direct mechanisms by which the mTOR pathway drives the progression of obesity related GI cancers have yet to be defined, there is substantial emerging evidence the mTOR is heavily implemented in these malignancies.

Fig. 3

Targeting the mTOR pathway. Specific target domains of mTOR and PI3K are highlighted at the point of inhibition.