Chapter 18 - Resistance to EGFR Targeting Treatments in Colorectal Cancer

Abstract

During the past three decades, epidermal growth factor receptor (EGFR) targeting has been intensely pursued as a treatment strategy for metastatic colorectal cancer. One approach uses monoclonal antibodies to inhibit the extracellular domain of EGFR, thus blocking natural ligands binding. Unfortunately, patients often develop resistance, with consequent growth of tumor burden and relapse. This chapter discusses some of the mechanisms responsible for the failure of current therapies. Tumor heterogeneity is addressed as the main culprit for multiple escaping mechanisms, reflecting the high level of molecular heterogeneity present in each metastatic site. Genetic as well as nongenetic mechanisms are discussed, including acquisition of activating mutations in the mitogen-activated protein kinase axis mediators, epithelial-to-mesenchymal transition, activation of EGFR feedback loops, and signaling reactivation and bypass. Finally, autocrine and microenvironment secretion of growth factors that aid proliferative and anti-apoptotic signaling are also reported. The chapter concludes with an introduction of some promising combinatorial approaches, developed to overcome resistance to EGFR blockage.