Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy

Abstract

Non-small cell lung cancer (NSCLC) is the major cause of cancer-related deaths in the USA and worldwide. Most patients present with advanced disease, and treatment options for these patients are generally limited to platinum-based chemotherapy and a few targeted therapies. Targeted agents currently in use for NSCLC inhibit oncogenic receptor tyrosine kinase pathways, such as the epidermal growth factor receptor (EGFR) pathway. While current EGFR-targeted agents, including erlotinib and gefitinib, may result in dramatic responses, they demonstrate efficacy in only a fraction of patients, and resistance to these agents frequently develops. In order to select patients most likely to benefit from blockade of EGFR pathways, investigators have focused on identifying molecular correlates of response to anti-EGFR therapy. New strategies to minimize the risk of resistance to EGFR inhibition have been employed in the development of next-generation EGFR tyrosine kinase inhibitors, such as PF00299804 and BIBW 2992; these include irreversibility of target binding, inhibition of multiple EGFR family receptors, and/or simultaneous inhibition of EGFR and other oncogenic pathways.

Fig. 1

Cellular effects resulting from activation of the EGFR pathway. EGFR signaling mediates the activation of a variety of cellular processes associated with carcinogenesis. All of the hallmarks of cancer are activated with the exception of limitless replicative potential

Fig. 2

Mechanisms of EGFR resistance to TKIs in NSCLCs. (a) illustrates TKI-sensitive EGFR, where inhibition results in abrogation of EGFR signaling. TKIs may be ineffective for inhibiting EGFR signaling if specific EGFR mutations, such as T790M (b), amplification of MET (c), or KRAS mutation (d) occurs. I would like to thank Dr. Lecia Sequist, MD, MPH, and Dr. Jeffrey Settleman, PhD, for suggestion of the concept for Fig. 2 illustration

Fig. 3

Potential targets for inhibition within the EGFR signaling pathway. Multiple points along the EGFR signaling pathway, indicated with arrows, are currently being evaluated as therapeutic targets in the treatment of NSCLC. Inhibition of EGFR activation can occur by targeting EGFR itself and/or its downstream mediators. Small molecule TKIs and other agents are shown associated with their respective targets. Figure adapted with permission from [12]