Tumor resistance to agents targeting the Epidermal Growth Factor Receptor
(EGFR) is common, and well recognised as a major challenge to successful clinical
outcome, because patients often present with tumors that contain pre-existing intrinsic
resistance mechanisms to current EGFR inhibitors, which ultimately has no therapeutic
benefit. Furthermore, patients who initially respond to these therapies commonly
relapse, presenting with new tumors that have acquired resistance to the original
therapy. Substantial translational and clinical research has been undertaken in order to
understand, and more importantly overcome, the molecular initiators of both intrinsic
and acquired tumor resistance. However, despite a multitude of cost and effort in
gaining greater understanding of the molecular mechanisms that drive tumor resistance,
very little has translated into clinical practice and management of patients. 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 II) we will specifically focus on the resistance
mechanisms mediated by alterations in substrates downstream of the EGFR and review
other intracellular mechanisms that mediate both sensitivity and resistance outcomes to
anti-EGFR agents.
Keywords: Afatinib, Cancer, Cetuximab, Epidermal Growth Factor Receptor, Erlotinib, Gefitinib, Lapatinib, Panitumumab, Resistance, Signaling, Therapeutics,
Tumor.
