KRAS and BRAF: drug targets and predictive biomarkers

Three decades have passed since RAS was first identified as the transformative factor in the Harvey and Kirsten strains of the mouse sarcoma virus. RAS and several of its downstream effectors, including BRAF, have since been shown to be commonly mutated in broad range of human cancers and biological studies have confirmed that RAS pathway activation promotes tumour initiation, progression and metastatic spread in many contexts. With the identification of RAS mutation as a strong predictor of clinical resistance to EGFR-targeted therapies, RAS mutational testing has been incorporated into the routine clinical care of patients with colorectal and lung cancers. This article reviews the current understanding of RAS signalling as it relates to cancer biology, current efforts to develop inhibitors of RAS and its key downstream effectors and the technical challenges of RAS mutational testing in the clinical setting.