Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer

Abstract

Administration of monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer (mCRC). However, the efficacy of these mAbs is limited due to genetic variation among patients, in particular K-ras mutations. The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC. Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF, MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors. Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation, our understanding of their mode of action is limited. Rational drug development based on stringent preclinical data, biomarker validation, and proper selection of patients is of paramount importance in the treatment of mCRC. In this review, we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFR-Ras-ERK and PI3K signalings.

Keywords: Colorectal cancer; Epidermal growth factor receptor; Resistance; K-ras mutation; Combinational therapy

Core tip: Personalized treatment of patients with metastatic colorectal cancer (mCRC) based on genetic profiling of individual tumors is considered the future direction of cancer therapy. The important discovery that mutation of the K-ras gene is a predictor of resistance to epidermal growth factor receptor (EGFR) monoclonal antibodies is only the first of a series of genetic predictors and an increasing number of molecular alterations have since been hypothesized to play a role in resistance to anti-EGFR drugs in CRC, including activating mutations in B-Raf and PIK3CA, and loss of expression of PTEN. A comprehensive molecular characterization of mCRC and a better understanding of the functional interactions within the RTK-activated intracellular pathway will be necessary in order to select the most appropriate therapy for each individual patient.