Targeting EGFR and RAS/RAF Signaling in the Treatment of Metastatic Colorectal Cancer: From Current Treatment Strategies to Future Perspectives

Abstract

The epidermal growth factor receptor (EGFR) and RAS/RAF signaling pathway plays pivotal roles in tumor progression via proliferation, survival, invasion, and immune evasion. Two anti-EGFR monoclonal antibodies, cetuximab and panitumumab, have become essential components in the treatment of patients with metastatic colorectal cancer (mCRC). Treatment with these anti-EGFR antibodies has shown definite benefits when administered in all treatment lines and is strongly recommended as the preferred regimen to prolong survival, especially when administered in the first- and third-lines. Recent efforts have revealed not only mechanisms responsible for resistance to anti-EGFR antibodies, including expanded RAS mutations as a negative predictive biomarker, but also the possibility of continuing anti-EGFR antibody treatment in combination with chemotherapy. Furthermore, the challenges associated with the pharmaceutical development of treatments for patients with mutant-type BRAF mCRC are ongoing. In this review, we provide an overview of the EGFR and RAS/RAF signaling pathway and antitumor activity, focusing on practical aspects such as established treatments including patient selection, treatment strategies, and future perspectives for drug development targeting the EGFR and RAS/RAF signaling pathway.