Molecularly targeted approaches herald a new era of non-small-cell lung cancer treatment

Abstract

The discovery of activating mutations in the epidermal growth-factor receptor (EGFR) gene in 2004 opened a new era of personalized treatment for non-small-cell lung cancer (NSCLC). EGFR mutations are associated with a high sensitivity to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib. Treatment with these agents in EGFR-mutant NSCLC patients results in dramatically high response rates and prolonged progression-free survival compared with conventional standard chemotherapy. Subsequently, echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK), a novel driver oncogene, has been found in 2007. Crizotinib, the first clinically available ALK tyrosine kinase inhibitor, appeared more effective compared with standard chemotherapy in NSCLC patients harboring EML4-ALK. The identification of EGFR mutations and ALK rearrangement in NSCLC has further accelerated the shift to personalized treatment based on the appropriate patient selection according to detailed molecular genetic characterization. This review summarizes these genetic biomarker-based approaches to NSCLC, which allow the instigation of individualized therapy to provide the desired clinical outcome.

Keywords: ALK rearrangement; crizotinib; epidermal growth factor receptor; erlotinib; gefitinib; non-small-cell lung cancer.

Figure 1

(A and B) Strategies to overcome acquired epidermal growth-factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance in non-small-cell lung cancer (NSCLC). (A) The T790M secondary mutation in exon 20 of EGFR is present in 50%–70% of NSCLC patients who acquire resistance to EGFR-TKIs, such as gefitinib or erlotinib. In such patients, gefitinib is not able to compete with adenosine triphosphate (ATP) for binding to the ATP-binding cleft of EGFR because of an increased affinity of this site for ATP. Treatment with irreversible EGFR-TKIs or EGFR-TKIs selective for EGFR harboring T790M is thus thought to represent a potential approach to overcome the resistance conferred by this mutation. (B) Amplification of MET is apparent in 5%–15% of NSCLC patients who acquire EGFR-TKI resistance. In this situation, MET signaling through ErbB3 (HER3) is activated in addition to EGFR signaling, with the result that both gefitinib and a MET inhibitor (such as PHA665752) are necessary to overcome the resistance conferred by MET amplification. The combination of inhibitors that block molecules that function downstream of both EGFR and MET, such as a phosphoinositide 3-kinase (PI3K) inhibitor combined with an MEK (ERK kinase) inhibitor, might also be an alternative approach to overcome the resistance induced by MET amplification.