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

  • Takuro Mizukami
  • Naoki Izawa
  • Takako Eguchi Nakajima
  • Yu SunakawaEmail author
Review Article


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.


Compliance with Ethical Standards


No external funding was used in the preparation of this manuscript.

Conflict of interest

Takuro Mizukami has received consulting fees from Merck Serono and a speaker honorarium from Merck Serono and Takeda Pharmaceutical Co. Ltd. Takako Eguchi Nakajima has received research grants from Merck Serono, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Eli Lilly Japan, and Sanofi KK and a speaker honorarium from Merck Serono, Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Eli Lilly Japan. Yu Sunakawa has received consulting fees from Takeda Pharmaceutical Co. Ltd. and a speaker honorarium from Takeda Pharmaceutical Co. Ltd. and Merck Serono. Naoki Izawa declares that he has no conflicts of interest that might be relevant to the contents of this manuscript.


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Clinical OncologySt. Marianna University School of MedicineKawasakiJapan

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