Advances of Targeted Therapy in Treatment of Unresectable Metastatic Colorectal Cancer

Abstract

Despite being one of the most frequently diagnosed cancers worldwide, prognosis of metastatic colorectal cancer (CRC) was poor. Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes. Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC. Encouraged by results from many clinical trials demonstrating efficacy of those monoclonal antibodies, the combination therapy with those targeted agents and conventional chemotherapeutic agents has been established as the standard therapy for patients with metastatic CRC. However, emergency of resistance to those target agents has limited the efficacy of treatment, and strategies to overcome the resistance are now being investigated by newly developed biological techniques clarifying how to acquire resistance. Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment. The mechanism of resistance to those agents, one of serious problems in treatment metastatic CRC, and ongoing clinical trials to overcome the limitations and improve treatment outcomes will also be presented in this review.

Figure 1

Signaling through EGFR. Signaling is initiated by interaction of ligands with EGFR. The resultant autophosphorylation of tyrosine kinase residues binds to the growth-factor-receptor-bound protein 2 (GRB2), and SOS is recruited to the plasma membrane. Subsequent activation of RAS activates RAS-RAF-MEK-MAPKs pathway. PI3Ks-AKT or RAS-PLCε-PKC are also known to be activated by signaling through EGFR. TM: transmembrane.