Resistance to EGFR Targeting Treatments in Colorectal Cancer

Over the last three decades, EGFR targeting has been intensely pursued as a treatment strategy for metastatic colorectal cancer. One approach uses monoclonal antibodies (mAbs) 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. In this chapter, we will discuss some of the mechanisms responsible for the failure of current therapies. Tumors heterogeneity will be 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 non-genetic mechanisms will be discussed. Among them acquisition of activating mutations in the MAPK axis mediators, epithelial-to-mesenchymal transition, activation of EGFR feedback loops and signalling reactivation and bypass. Finally, autocrine and microenvironment secretion of growth factors that aids proliferative and antiapoptotic signalling, are also reported. We conclude with an introduction of some promising combinatorial approaches, developed to overcome resistance to EGFR blockage.