Targeted therapies in development for non-small cell lung cancer

Abstract

The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), MAPK (mitogen-activated protein kinase) c-MET (c-mesenchymal-epithelial transition), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha)), PTEN (phosphatase and tensin homolog), AKT (protein kinase B), ALK (anaplastic lym phoma kinase), RET (rearranged during transfection), ROS1 (reactive oxygen species 1) and EPH (erythropoietin-producing hepatoma) are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4)-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and advantageous in overcoming treatment resistance compared with monotherapy approaches. Understanding the role of the tumor microenvironment in the development and maintenance of the malignant phenotype provided additional therapeutic approaches as well. More recently, improved knowledge on tumor immunology has set the stage for promising immunotherapies in NSCLC. This review will focus on the rationale for the development of targeted therapies in NSCLC and the various strategies employed in preventing or overcoming the inevitable occurrence of treatment resistance.

Keywords: Drug resistance; heat shock protein 90 inhibitors; non-small cell lung cancer; programmed cell death-1 receptor inhibitors; protein kinase inhibitors.

Figure 1

Cell signaling pathways in lung cancer. Depicted are the cellular signaling pathways involved in the proliferation, differentiation, growth, metastasis, resistance to apoptosis and angiogenesis in neoplasms, highlighting the targets amenable to therapeutic interventions in lung cancer therapy. Membrane-bound members of the ErbB family of receptors, MET, VEGFR and IGF-1R mediate mitogenic signals from extracellular ligands, such as EGF, HGF, VEGF and IGF, respectively. The Ras/Raf/MEK/ERK (mitogen-activated protein kinase, MAPK) and PI3K/AKT/mTOR pathways are major intracellular axes that regulate intracellular signaling traffic (AKT: Protein kinase B, AMPK-1: 5’-AMP-activated protein kinase catalytic subunit alpha-1, EGF: Epidermal growth factor, EGFR: Epidermal growth factor receptor, eIF-4F: Eukaryotic initiation factor-4 complex, EML4-ALK: Echinoderm microtubule-associated protein-like 4 fused with the anaplastic lymphoma kinase, ERK: Extracellular signal-regulated kinases, 4E-BP1: 4E binding protein-1, GAP: GTPase; activating protein, GDP: Guanosine diphosphate, GEF: Guanine nucleotide exchange factors, GRB2: Growth factor receptor-bound protein 2, GTP: Guanosine triphosphate, HER: Human epidermal growth factor receptors, HGF: Hepatocyte growth factor, IGF: Insulin growth factors, IGF-1R: Insulin-like growth factor 1 receptor, IRS: Insulin receptor substrate, MEK: Mitogen-activated protein kinase, mTOR: Mammalian target of rapamycin, PDK1: 3-phosphoinositide – dependent protein kinase 1, PI3K: Phosphatidylinositide 3-kinase, PTEN: Phosphatase and tensin homolog, rpS6: Ribosomal protein S6, S6K1: 40S ribosomal protein S6 kinase, SHC: Src homology/collagen, SOS: Son of sevenless, TSC: Tuberous sclerosis; VEGFR: Vascular endothelial growth factor receptor)