Cancer drug resistance induced by EMT: novel therapeutic strategies

Abstract

Over the last decade, important clinical benefits have been achieved in cancer patients by using drug-targeting strategies. Nevertheless, drug resistance is still a major problem in most cancer therapies. Epithelial-mesenchymal plasticity (EMP) and tumour microenvironment have been described as limiting factors for effective treatment in many cancer types. Moreover, epithelial-to-mesenchymal transition (EMT) has also been associated with therapy resistance in many different preclinical models, although limited evidence has been obtained from clinical studies and clinical samples. In this review, we particularly deepen into the mechanisms of which intermediate epithelial/mesenchymal (E/M) states and its interconnection to microenvironment influence therapy resistance. We also describe how the use of bioinformatics and pharmacogenomics will help to figure out the biological impact of the EMT on drug resistance and to develop novel pharmacological approaches in the future.

Keywords: Cancer; Epithelial plasticity; Therapy resistance; Tumour microenvironment.

Fig. 1

Targeting cancer epithelial tumour plasticity to overcome resistance. Tumour cells with epithelial phenotype can undergo epithelial-to-mesenchymal transition program at primary tumour site. Epithelial cells loose cell–cell contacts and aquiere invasive and migratory capabilities. The existence of intermediate epithelial/mesenchymal marker proteins in cancer cells with partial E/M hybrid phenotype is associated with increased cellular plasticity and stemness. Several transcription factors, post-trasncriptional and post-translational regulators of the EMT are implicated in therapy resistance

Fig. 2

Microenvironment drivers of the EMT as potential therapeutic target to overcome therapy resistance. Several microenvironment factors such as tumour associated macrophages (TAMs), cancer associated fibroblasts (CAFs), alterations in the extracellular matrix (ECM), hypoxic conditions, inflammatory and immune cells are EMT-drivers. These cells activate several signaling pathways such as TNF-α, TGF-β, IL-1β, IL-6, VEGF, HGF, HIFs, NOTCH and WNT, inducing EMT-transcription factors