Lung cancer is the leading cause of cancer mortality in the United States and worldwide, accounting for 28% of cancer-related deaths in males and 26% of cancer-related deaths in females [1
]. Most lung cancer patients present with advanced stage disease, for which conventional chemotherapies patients are only modestly effective. Thus, the 5-year-survival rate of lung cancer patients with metastatic disease is less than 15% [3
]. In the last decade, the discovery of mutated oncogenes that encode activated signaling molecules that drive cellular proliferation and promote tumor growth has led to the development of more effective and less toxic targeted drugs for lung cancer patients. Systemic therapies that act against specific activated oncogenes in lung cancers have the potential for improving outcomes for lung cancer patients in an unprecedented manner. Yet, a significant challenge that must be overcome in order to realize the full potential of targeted cancer therapy in lung cancer patients is resistance to treatment with an oncogene inhibitor as monotherapy.
The epidermal growth factor receptor (EGFR) is a well-characterized mutated oncogene in non-small cell lung cancer (NSCLC) that is found in ~10–20% of cases in western countries and is associated predominantly with adenocarcinoma histology. EGFR-mutated tumors are dependent to EGFR signaling for their proliferation and survival [4
]. In lung cancer patients, EGFR mutations are generally exclusive with KRAS and BRAF mutations, and tumors with either KRAS (15–25%) or BRAF (2-3%) mutations are relatively insensitive to EGFR TKIs [8
]. The most common activating mutations (~90%) are in-frame deletions in exon 19 of EGFR and a missense mutation at 858 in exon 21 of EGFR resulting in an arginine to leucine substitution (L858R) [10
]. Therapeutic agents targeting the EGFR signaling pathway, including two EGFR kinase inhibitors gefitinib and erlotinib, are clinically effective in treating lung cancer patients harboring these EGFR activating mutations [11
Despite the dramatic efficacy of EGFR TKIs in NSCLC patients with EGFR activating mutations, unfortunately, de novo resistance to TKIs is observed and virtually all patients who initially respond will ultimately develop acquired resistance. In this paper, we focus on the mechanisms of both de novo resistance (lack of an initial response to therapy) and acquired resistance (resistance that develops following an initial response to therapy) to EGFR TKIs. We also discuss potential strategies to overcome resistance in lung cancer patients. It is currently not known whether acquired resistance occurs through clonal selection of resistant tumor cells present in the initial tumor or is induced during therapy. Approaches such as lineage tracing or next generation deep sequencing at the single-cell level could be used to address this unresolved issue.