The role of MET in chemotherapy resistance

Abstract

Chemotherapy remains the mainstay of treatment in the majority of solid and haematological malignancies. Resistance to cytotoxic chemotherapy is a major clinical problem and substantial research is ongoing into potential methods of overcoming this resistance. One major target, the receptor tyrosine kinase MET, has generated increasing interest with multiple clinical trials in progress. Overexpression of MET is frequently observed in a range of different cancers and is associated with poor prognosis. Studies have shown that MET promotes resistance to targeted therapies, including those targeting EGFR, BRAF and MEK. More recently, several reports suggest that MET also contributes to cytotoxic chemotherapy resistance. Here we review the preclinical evidence of MET's role in chemotherapy resistance, the mechanisms by which this resistance is mediated and the translational relevance of MET inhibitor therapy for patients with chemotherapy resistant disease.

Fig. 1. MET signalling.

HGF binding to MET triggers MET dimerisation and phosphorylation. Several signalling pathways are then activated, leading to the activation of signals including ERK1/2, STAT3, PI3K and Rac1. Cells respond in increasing their proliferation, migration and/or survival. In parallel, HGF binding to MET triggers its internalisation. MET is still bound to HGF and continues to signal on endosomes. MET internalisation has been shown to be required to sustain its signalling. MET slowly gets degraded, leading to signal termination but oncogenic MET mutants are protected against degradation and trigger persistent endosomal signalling, contributing to their oncogenicity.

Fig. 2. Model of MET-driven chemoresistance.

Chemotherapy resistant cancer cells (CRCC) have altered MET signalling, including overexpression of MET, activation sustained by HGF secreted by CAFs (cancer associated fibroblasts), constitutive activation of MET and secretion of HGF which is not normally expressed by epithelial cells, leading to an autocrine activation loop. This diagram illustrates the effect of this altered MET signalling on: (i) the behaviour of CRCCs: reduction of apoptosis, increased proliferation, enhanced DNA repair, upregulation of drug efflux and stimulation of epithelial-mesenchymal transition; (ii) changes in the tumour microenvironment: alteration of the behaviour of endothelial cells and increased intra-tumoural hypoxia, promotion of cancer stem cells (CSCs) survival and proliferation. All these changes contribute to the development of chemotherapy resistance. The intracellular pathways reported or suggested are shown. Blue box/black line: confirmed mechanism. Dotted red box/red line: proposed mechanism. MMPs matrix metallopeptidases, VEGF vascular endothelial growth factor, AIF apoptosis-inducing factor, ER endoplasmic reticulum.