Since its discovery several decades ago, the Epidermal Growth Factor
Receptor (EGFR) has become one of the most extensively studies receptor tyrosine
kinases. However, despite continued insight into the cancer promoting properties of the
EGFR and its downstream signalling substrates, clinical use of agents targeting the
EGFR continue to yield modest outcomes. Clinically, approved anti-EGFR therapeutics
can successfully inhibit receptor activation. However major tumour regression is
observed in only 10-30% of advanced unselected cancer patients, with most patients
showing no therapeutic benefit. Furthermore, those who initially respond commonly
relapse presenting with reoccurrence of tumours that are frequently resistant to the
original therapy. In addition, the standard course of treatment of such agents is
estimated to cost between “US $15,000-80,000/patient” for an improved overall
survival of only 1-2 months. Therefore, it is both medically and financially critical to
determine the true molecular mechanisms of tumour resistance, and how it can be
overcome. In these 2 back-to-back chapters, we will provide an overview of the
progress made in targeting the EGFR and discuss the challenges presented by the
numerous molecular mechanisms currently identified, leading to overall refractory
outcomes to anti-EGFR therapeutics. In this chapter (Part I) we will specifically focus
on the resistance mechanisms driven by alterations in ligand and receptors of the EGFR
family and cross-talk between EGFR receptors and non-EGFR family members.
Keywords: Afatinib, Cancer, Cetuximab, Epidermal Growth Factor Receptor, Erlotinib, Gefitinib, Lapatinib, Panitumumab, Resistance, Signaling, Therapeutics,
Tumor.
