Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer

Abstract

The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase III clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them.

Keywords: BRAF; Epidermal growth factor receptor; KRAS; MET; Metastatic colorectal cancer; Monoclonal antibodies; Mutation; NRAS; PIK3CA; Resistance.

Figure 1

Epidermal growth factor receptor and its downstream signaling pathway. Binding of ligands such as epidermal growth factor (EGF) to Epidermal growth factor receptor (EGFR) activates downstream Ras/ERK and PI3K/Akt pathways and regulates various physiological processes. The anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab block the activation of these pathways.

Figure 2

Mechanisms of resistance to anti-epidermal growth factor receptor monoclonal antibodies in metastatic colorectal cancer. A: Activating mutations of EGFR effectors, such as RAS, BRAF and PI3KCA, or PTEN loss of function, cause persistent activation of downstream signaling regardless of EGFR inhibition; B: Mutations in extracellular domain of EGFR inhibit cetuximab binding, but not panitumumab, mediating acquired resistance. Mutations in kinase domain of EGFR led pathways activation in the context of acquired resistance; C: Amplification/activation of alternative receptors such as HER2 or MET, can bypass the EGFR blockade and mediate pathways activation. EGFR: Epidermal growth factor receptor.