Signal Transduction Pathways of the Epidermal Growth Factor Receptor in Colorectal Cancer and their Inhibition by Small Molecules

While prognostic factors can help to classify the standard risk of subpopulations of patients with the same tumor entity, it is still not possible to predict the response of individual patients to specific therapies. The reason for such wide variation in cancer therapy responses remains largely unknown. The field of chemotherapy is currently undergoing a paradigm shift from classical cytotoxic chemotherapy to targeted therapy in order to kill tumor cells more efficiently with fewer side effects on normal tissue. In the present review, we focus on colorectal carcinoma, which is one of the most frequent tumor types worldwide and represents a leading cause of cancer-related deaths. The signaling pathways downstream of epidermal growth factor receptor (EGFR) are central to the biology of colorectal cancer. A considerable achievement during the past years was the development of targeted therapies against EGFR using monoclonal antibodies and small molecule inhibitors. Two major pathways mediate signal transduction through EGFR: the RAS/RAF/MAPK/ERK and the PI3K/AKT/PTEN/mTOR pathways. Sometimes, predictive biomarkers can provide information on the expected response of tumors to standard chemotherapy. Such molecular markers for EGFR-targeted treatment have been described. However, disease progression and resistance towards EGFR-directed drugs frequently develop due to mutations in genes downstream of EGFR. In this review, we describe the mechanisms by which colorectal cancers gain resistance against EGFR-targeted therapies as well as strategies to bypass mutation-induced resistance in these two signaling pathways.