Molecular Targeted Drugs and Biomarkers in NSCLC, the Evolving Role of Individualized Therapy

Kalliopi Domvri, Paul Zarogoulidis, Kaid Darwiche, Robert F Browning, Qiang Li, J Francis Turner, Ioannis Kioumis, Dionysios Spyratos, Konstantinos Porpodis, Antonis Papaiwannou, Theodora Tsiouda, Lutz Freitag, Konstantinos Zarogoulidis, Kalliopi Domvri, Paul Zarogoulidis, Kaid Darwiche, Robert F Browning, Qiang Li, J Francis Turner, Ioannis Kioumis, Dionysios Spyratos, Konstantinos Porpodis, Antonis Papaiwannou, Theodora Tsiouda, Lutz Freitag, Konstantinos Zarogoulidis

Abstract

Lung cancer first line treatment has been directed from the non-specific cytotoxic doublet chemotherapy to the molecular targeted. The major limitation of the targeted therapies still remains the small number of patients positive to gene mutations. Furthermore, the differentiation between second line and maintenance therapy has not been fully clarified and differs in the clinical practice between cancer centers. The authors present a segregation between maintenance treatment and second line and present a possible definition for the term "maintenance" treatment. In addition, cancer cell evolution induces mutations and therefore either targeted therapies or non-specific chemotherapy drugs in many patients become ineffective. In the present work pathways such as epidermal growth factor, anaplastic lymphoma kinase, met proto-oncogene and PI3K are extensively presented and correlated with current chemotherapy treatment. Future, perspectives for targeted treatment are presented based on the current publications and ongoing clinical trials.

Keywords: NSCLC; maintenance; pathways; targeted treatment.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
IGF-1; insulin growth factor-1, IGF-1R; insulin growth factor receptor-1, EGF; epidermal growth factor, EGFR; epidermal growth factor receptor, VEGF; vascular endothelial growth factor, VEGFR; vascular endothelial growth factor receptor, PI3K; phosphatidylinositide 3-kinase, PTEN; phosphatase and tensin homologue, SHC; Src homology/collagen, SOS; son of sevenless, GRB2; growth factor receptor-bound protein 2, GAP; GTPase activating protein, GDP; guanosine diphosphate, GEF; guanine nucleotide exchange factors, EML4-ALK; echinoderm microtubule-associated protein-like 4 fused with the anaplastic lymphoma kinase, ERK; extracellular signal-regulated kinases, GTP; guanosine trisphate, MEK; mitogen-activated protein kinase, RAF; proto-oncogene serine/threonine-protein kinase, PIP2; phosphatidylinositol 4,5-bisphosphate, PIP3; phosphatidylinositol 3,4,5-triphosphate, RAS; Rat sarcoma, HER2; Human Epidermal Growth Factor Receptor 2. Activation of the growth factors to transmembrane tyrosine kinase receptors finally increases cell growth, proliferation, metabolism and survival.
Figure 2
Figure 2
TKI; tyrosine kinase inhibitors, S6K1; 40S ribosomal protein S6 kinase, IRS1/2; insulin receptor substrate, 4E-BP1; 4E binding protein-1, Akt; protein kinase B, mTOR; mammalian target of rapamycin, STRAD; Ste20-like adaptor protein, TSC; tuberous sclerosis complex, AMPK; adenosine mono-phosphate-activated protein kinase, LKB1; liver kinase B1, HGF; hepatocyte growth factor, MET; mesenchymal-epithelial transition factor, Rho; RAS homolog gene family, Rac1; RAS-related C3 botulinum toxin substrate 1, CDC42; cell division cycle 42, Rheb; Ras homolog enriched in brain, MO25; monoclonal antibody, ERBB3; v-erb-b2 erythroblastic leukemia viral oncogene homolog 3. Growth factors when activated trigger the mTOR-signaling pathway finally resulting in increased cell growth, gene transcription and cell proliferation.

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