Addressing the tumour microenvironment in early drug discovery: a strategy to overcome drug resistance and identify novel

The tumour microenvironment (TME) comprises not only malignant and non-malignant cells, but also the extracellular matrix (ECM), secreted factors, and regulators of cellular functions. In addition to genetic alterations, changes of the biochemical/biophysical properties or cellular composition of the TME have been implicated in drug resistance. Here, we review the composition of the ECM and different elements of the TME contributing to drug resistance, including soluble factors, hypoxia, extracellular acidity, and cell adhesion properties. We discuss selected approaches for modelling the TME, current progress, and their use in low and high-throughput assays for preclinical studies. Lastly, we summarise the status quo of advanced 3D cancer models compatible with high throughput screening (HTS), the technical practicalities and challenges. The tumour microenvironment (TME) comprises not only malignant and non-malignant cells, but also the extracellular matrix (ECM), secreted factors, and regulators of cellular functions. In addition to genetic alterations, changes of the biochemical/biophysical properties or cellular composition of the TME have been implicated in drug resistance. Here, we review the composition of the ECM and different elements of the TME contributing to drug resistance, including soluble factors, hypoxia, extracellular acidity, and cell adhesion properties. We discuss selected approaches for modelling the TME, current progress, and their use in lowand high-throughput assays for preclinical studies. Lastly, we summarise the status quo of advanced 3D cancer models compatible with highthroughput screening (HTS), the technical practicalities and challenges.

Automated summary

This article reviews the composition of the tumour microenvironment, including the ECM and different elements contributing to drug resistance. It discusses approaches for modelling the TME, current progress, and their use in low and high-throughput assays for preclinical studies, summarising the status quo of advanced 3D cancer models compatible with high throughput screening and the technical practicalities and challenges.