Targeting the EGFR/RAS/RAF signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023)

Recent years have witnessed great achievements in drug design and development targeting the epidermal growth factor receptor EGFR/RAS/RAF signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for EGFR, RAS, and RAF proteins show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of EGFR, RAS, and RAF proteins in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of forty-two inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions to improve efficacy and to overcome drug resistance for these three target proteins are also discussed.