Archives of Science
Open Access

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) which directs the expansion of disease cells particularly non-small cell lung cancer (NSCLC). NSCLC development is restrained by EGFR tyrosine kinase inhibitors (TKI, for example, erlotinib or gefitinib. Gefitinib is utilized to treat NSCLC patients who have EGFR changes. EGFR tyrosine phosphorylation is controlled by G protein-coupled receptors (GPCR, for example, the neurotensin (NTS) receptor. EGFR transactivation made by NTS expansion NSCLC cells is restrained by SR48692 (NTSR1 adversary) or gefitinib. SR48692 and gefitinib are synergistic at restraining NSCLC multiplication. The outcomes show that GPCR adversaries can potentiate the impacts of TKI in cancer.

High groupings of receptor tyrosine kinases (RTK, for example, the Epidermal Development Element Receptor (EGFR, erbB1) are available in specific cancers such as non-small cell lung cancer (NSCLC) [1]. In the wake of restricting ligands, for example, EGF, heparin binding (HB-EGF), changing development factor (TGF α) or amphiregulin, the EGFR can frame homodimers with itself or heterodimers with other receptor tyrosine kinases (RTK) like HER2 (erbB2) [2]. This increments tyrosine phosphorylation of protein substrates, for example, the mitogen actuated protein kinase (MAPK) or phosphatidylinositol-3 kinase (PI3K) prompting expanded malignant growth cell multiplication and endurance [3].

NSCLC, which kills around 130,000 residents yearly in the USA, is traditionally treated with mix chemotherapy; however the 5-year endurance rate is just 16% [1]. Around 13% of the NSCLC patients have transformed EGFR because of exon 19 deletions or exon 21 mutations, for example, L858R [4]. The mutated EGFR has expanded tyrosine kinase action bringing about the tyrosine phosphorylation of the EGFR. The patients with changed EGFR can be treated with tyrosine kinase inhibitors (TKI, for example, gefitinib or erlotinib, however following a year optional EGFR transformations can happen, for example, T790 M bringing about TKI resistance [4]. There is a need to build the responsiveness of NSCLC patients to TKI.

The phosphorylation of the EGFR is controlled by G proteincoupled receptors (GPCR) for neurotensin (NTS) inside the space of minutes after expansion of ligand to NSCLC cells [5]. The declaration of RTK, for example, ErbB1, ErbB2 or ErbB3 is expanded by NTS days after expansion to NSCLC cells [6]. The tyrosine phosphorylation of the EGFR made by NTS expansion NSCLC cells is impeded by the NTSR1 antagonist SR48692 and the TKI gefitinib. In this correspondence, the system by which NTS causes EGFR transactivation is surveyed.

NTS ligand

Neurotensin (NTS) is a 13 amino acid peptide which is organically dynamic in the central nervous system (CNS). When let out of hypothalamic brain neurons, NTS causes absence of pain, hypothermia and balances dopamine signaling in the CNS [7]. NTS might be a neuromodulator in the CNS whereby it is released from brain neurons and enacts receptors in adjacent cells. In cancer, NTS is an autocrine development factor. NTS is abundant in small cell lung cancer (SCLC) [8] and medullary thyroid carcinoma. NTS is discharged from SCLC and binds with high affinity to SCLC cells. The activity of NTS is intervened by NTSR1 in cancer cells and NTS animates the development of SCLC cells. SR48692 is a non-peptide NTSR1 antagonist which hinders the multiplication of pancreatic, prostate and SCLC cells in vitro and in vivo.

NTS is synthesized as a 170 amino corrosive forerunner protein (prepro-NTS) which lacks biological activity. A sign protease divides prepro-NTS to pro NTS (147 amino acids) which is inactive. A proprotein convertase enzyme and carboxypeptidase cleaves pro-NTS to NTS (13 amino acids) which is organically dynamic and Neuromedin N (5 amino acids). The C-terminal hexapeptide of NTS (NTS8-13) is naturally dynamic. Corruption of NTS at the Arg8-Arg9 or Pro10- Tyr11 amide bonds by endopeptidases leads to inactive products. NTS is emitted from the SCLC cells when the cell cAMP is raised. The emitted NTS ties to cell surface receptors causing an autocrine SCLC multiplication.

Acknowledgement

None

Conflict of Interest

None

1. George AJ, Hannan RD, Thomas WG (2013) Unravelling the molecular complexity of GPCR-mediated EGFR transactivation using functional genomics approaches. FEBS J 280: 5258-5268.

Indexed at, Google Scholar, Crossref

2. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141: 1117-1134.

Indexed at, Google Scholar, Crossref

3. Lopes GL, Vattimo EFQ, Junior GDC (2015) Identifying activating mutations in the egfr gene: prognostic and therapeutic implications in non-small cell lung cancer. J Bras Pneumol 41: 365-375.

Indexed at, Google Scholar, Crossref

4. Moody TW, Chen DC, Mantey SA, Moreno P, Jensen RT (2014) SR48692 inhibits non-small cell lung cancer proliferation in an EGF receptor-dependent manner. Life Sci 100: 25-34.

Indexed at, Google Scholar, Crossref

5. Younes M, Wu Z, Dupouy S, Lupo AM, Mourra N, et al. (2014) Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib. Oncotarget 5: 8252-8269.

Indexed at, Google Scholar, Crossref

6. Carraway R, Leeman SE (1978) The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalamus. J BiolChem 248: 6854-6861.

Indexed at, Google Scholar


7. Moody TW, Carney DN, Korman LY, Gazdar A, Minna JD (1985) Neurotensin is produced by and secreted from classic small cell lung cancer cells. Life Sci 36: 1727-1736.

Indexed at, Google Scholar, Crossref

8. Zeytinoglu FN, Gabel RF, Tashjian AH, Hammer RA, Leeman SE (1980) Characterization of neurotensin production in medullary thyroid cells. Proc Natl Acad Sci U S A 77: 3741-3745.

Indexed at, Google Scholar, Crossref