Current and Future Approaches to Target the Epidermal Growth Factor Receptor and Its Downstream Signaling in Metastatic Colorectal Cancer.

The discovery of the key role of the epidermal growth factor receptor (EGFR) and its downstream signaling effectors in the pathophysiology of colorectal cancer (CRC) has ushered in the clinical use of targeted therapies in the treatment of metastatic CRC (mCRC). The anti-EGFR monoclonal antibodies cetuximab and panitumumab improve overall survival when combined with chemotherapy in first-line treatment of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) wild type mCRC and also improve progression-free survival and response rate in first-line treatment and treatment of refractory mCRC. There are ongoing efforts to discover mechanisms of innate and acquired resistance to anti-EGFR therapies in KRAS wild type mCRC patients and to take therapeutic advantage of this knowledge by using rational combinations of targeted therapies. In this review we will discuss the evidence for current use of anti-EGFR therapies and several recent and ongoing investigations to refine treatment for KRAS wild type mCRC, including more complete inhibition of the EGFR, HER2 inhibition, and MET proto-oncogene, receptor tyrosine kinase (MET) inhibition.