Importance of molecular features of non-small cell lung cancer for choice of treatment

Abstract

Lung cancer is the leading cause of cancer-related deaths in the United States. Approximately 85% of lung cancer is categorized as non-small cell lung cancer, and traditionally, non-small cell lung cancer has been treated with surgery, radiation, and chemotherapy. Targeted agents that inhibit the epidermal growth factor receptor pathway have been developed and integrated into the treatment regimens in non-small cell lung cancer. Currently, approved epidermal growth factor receptor inhibitors include the tyrosine kinase inhibitors erlotinib and gefitinib. Molecular determinants, such as epidermal growth factor receptor-activating mutations, have been associated with response to epidermal growth factor receptor tyrosine kinase inhibitors and may be used to guide treatment choices in patients with non-small cell lung cancer. Thus, treatment choice for patients with non-small cell lung cancer depends on molecular features of tumors; however, improved techniques are required to increase the specificity and efficiency of molecular profiling so that these methods can be incorporated into routine clinical practice. This review provides an overview of how genetic analysis is currently used to direct treatment choices in non-small cell lung cancer.

Figure 1

Targeting of NSCLC by VEGF inhibitors and EGFR TKIs. Bevacizumab, a monoclonal antibody, recognizes VEGF and prevents it from binding to the VEGFR which disrupts angiogenesis, halting tumor growth and metastasis. Sorafenib disrupts angiogenesis by inhibiting multiple receptors, including VEGFR, PDGFR-β, and RAF-1, as well as Flt3 and c-kit (not shown). Erlotinib and gefitinib reversibly bind to and inhibit the tyrosine kinase domain of the EGFR, cetuximab reversibly binds to the ligand-binding domain of the EGFR, and afatinib and PF00299804 irreversibly bind to and inhibit the tyrosine kinase domain of the EGFR to disrupt tumor proliferation and survival. Akt, protein kinase B; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PDGF-β, platelet-derived growth factor-β; PDGFR, platelet-derived growth factor receptor; PIK3, phosphatidylinositol 3-kinase; Raf-1, v-raf 1 murine leukemia viral oncogene homolog 1; Ras, retrovirus-associated DNA sequences; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.