The Transactivation of the Erbb Family of Receptor Tyrosine Kinases Is Regulated by Neurotensin Receptors in Cancer ErbB receptor transactivation

Main Article Content

Terry William Moody


Neurotensin (NTS)-like peptides are autocrine growth factors for lung cancer.  NTS is present in and secreted from lung cancer cells and binds to G protein-coupled receptors causing signal transduction and proliferation.  The growth of non-small cell lung cancer (NSCLC) cells is stimulated by NTS and inhibited by SR48692, a small molecule NTSR1 antagonist.  Adding NTS to NSCLC cells increases the tyrosine phosphorylation of ErbB receptor tyrosine kinases EGFR, HER2, and HER3 by transactivation.   The NTSR1 regulation of EGFR, HER2, and HER3 transactivation is blocked by SR48692, specific tyrosine kinase inhibitors, and certain monoclonal antibodies.  Additional agents which impair the transactivation process include PP2 (Src inhibitor), GM6001 (matrix metalloprotease inhibitor), and N-acetyl-cysteine (antioxidant).  The results indicate growth stimulation caused by the adding NTS to NSCLC cells may be mediated by transactivation of ErbB RTKs.

Keywords: neurotensin, SR48692, EGFR, HER2, HER3

Article Details

How to Cite
MOODY, Terry William. The Transactivation of the Erbb Family of Receptor Tyrosine Kinases Is Regulated by Neurotensin Receptors in Cancer. Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 13 july 2024. doi:
Review Articles


1. Daub H, Weiss FU, Wallasch C, Ullrich A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 1996; 379: 557-560.
2. Guha S, Rey O, Rozengurt E. Neurotensin induces protein kinase C-dependent protein kinase D activation and DNA synthesis in human pancreatic carcinoma cell line PANC-1. Cancer Res. 2002; 62: 1632-1640.
3. Hassan S, Dobner PR, Carraway RE. Involvement of MAP kinase, PI-3-Kinase and EGF-receptor in the stimulatory effect of neurotensin on DNA synthesis in PC3 cells. Regul Pept 2004; 120: 155-166.
4. Moody TW, Chan DC, Mantey SA, Moreno P, Jensen RT. SR48692 inhibits non-small cell lung cancer proliferation in an EGFR receptor-dependent manner. Life Sci. 2014; 100: 25-34.
5. Ehlers RA, Zhang Y, Hellmich MR, Evers BM. Neurotensin-mediated activation of the MAPK pathways and AP-1 binding in the human pancreatic cancer cell line MIA PaCa-2. Biochem Biophys Res Commun 2000; 269: 704-708.
6. Moody TW, Chiles J, Casibang M, Moody E, Chan D, Davis TP. SR48692 is a neurotensin receptor antagonist which inhibits the growth of small cell lung cancer cells. Peptides 2001; 22: 109-115.
7. Younes M, Wu Z, Dupouy S, Lupo AM, Mourra N, Takahashi T et al. 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 2014; 5: 8252-8269.
8. Wang Z. ErbB receptors and cancer. Methods Mol Biol, 2017; 1652: 3-35.
9. Roskoski R Jr. Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacologic Res 2019; 139: 395-411.
10. Reinmuth N, Brandt B, Kunze WP, Junker K, Thomas M, Achatzy R et al., Ploiyd, expression of erbB1, erbB2, p53 and amplification of erbB1, erbB2 and erbB3 in non- small cell lung cancer. Eur J Respir J 2000 16: 991-996.
11. Esparis-Ogando A, Montero JC, Arribas J, Ocana A, Pandiella A. Targeting the EGF/HER Ligand-Receptor System in Cancer. Curr Pharm Des 2016; 22: 5887-5898.
12. Yarden Y, Pines G. The ERBB network: At last, cancer therapy meets system biology. Nat Rev/Cancer 2012; 12: 553-563.
13. Karachaliou N, Lazzari C, Verlicchi A, Sosa AE, Rosell R. HER3 as a therapeutic target in cancer. BioDrugs 2017; 31: 63-73.,
14. Mishra R, Patel H, Alanazi S, Yuan L, Garrett JT. HER3 signaling and targeted therapy in cancer. Oncol Rev 2018; 12: 355.
15. Mota JM, Collier KA, Costa RL, Taxter T, Kalyan A, Leite CA et al., A comprehensive review of heregulins, HER3 and HER4 as potential therapeutic targets in cancer. Oncotarget 2017; 8: 89284-89306.
16. Wali VB, Gilbert-Hebert M, Mamillapalli, R, Haskins, JW, Kurppa, KJ, Elenius, K et al. Overexpression of ErbB4 JM-a CYT-1 and CYT-2 isoforms in transgenic mice reveals isoform-specific roles in mammary gland development and carcinogenesis. Breast Cancer Research 2014; 16:501.
17. Boules M, Li Z, Smith K, Fredrickson P, Richelson E. Diverse roles of neurotensin agonists in the central nervous system. Front Endocrinol 2013; 4: 36
18. Iyer MR, Kunow G. Therapeutic approaches targeting the neurotensin receptors. Expert Opin Ther Pat 2021; 31: 361-386.
19. Li, J, Song J, Zaytseva YY, Liu Y, Rychahou P, Jiang K et al. An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature 2016; 533: 411-415.
20. Carraway R, Leeman SE. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalamus. J Biol Chem 1973; 248: 6854-6861.
21. Moody TW, Carney DN, Korman LY, Gazdar AF, Minna JD. Neurotensin is produced and secreted by classic small cell lung cancer cells. Life Sci 1985; 36: 1727-1732.
22. Wood SM, Wood JR, Ghatei MA, Lee YC, O’Shaughnessy D, Bloom SR. Bombesin, somatostatin and neurotensin-like immunoreactivity in bronchial carcinoma. J Clin Endocrinol 1981; 53: 1310-1312.
23. Wu Z, Fournel L, Stadler N, Liu J, Boullier A, Hoyeau N et al. Modulation of lung cancer cell plasticity and heterogeneity with restoration of cisplatin sensitivity by neurotensin antibody. Cancer Lett 2019; 444: 147-161.
24. Gully D, Canton M, Boigegrain R, Jeanjean F, Molimard JC, Poncelet M et al. Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor. Proc Natl Acad Sci USA 1993; 90: 65-69.
25. Kitabgi P. Functional domains of the subtype 1 neurotensin receptor (NTS1). Peptides 2006; 27: 2461-2468.
26. Reubi JC, Waser B, Schaer JC, Laissue JA. Neurotensin receptors in human neoplasms: High incidence in Ewing’s sarcomas. Int J Cancer 1999; 82: 213-218.
27. Carraway RE, Plona AM. Involvement of neurotensin in cancer growth: Evidence, mechanism and development of diagnostic tools. Peptides 2006; 27: 2445-2460.
28.Souaze F, Viardot-Foucault V, Roullet N et al. Neurotensin receptor 1 gene activation by the Tcf/beta-catenin pathway is an early event in human colonic adenomas. Carcinogenesis 2006; 27: 708-716.
29. Chalon P, Vita N, Kaghad, Guillemot M, Bonnin J, Delpech B et al. Molecular cloning of a levocabastine-sensitive neurotensin binding site. FEBS Lett 1996; 386: 91-94.
30. Saada S, Marget P, Fauchail A, Lie MC, Chemin G, Sindou P et al. Differential expression of neurotensin and specific receptors. NTSR1 and NTSR2 in normal and malignant human B lymphocytes. J Immunol. 2012; 189: 5293-5303
31. Ghaemimanesh F, Mehravar M, Milani S, Poursani EM, Saliminejad K. The multifaceted role of sortilin/neurotensin receptor 3 in human cancer development. J Cell Physiol. 2021; 236: 6271-6281.
32. Ocejo-Garci M, Ahmed SI, Coulson JM, Woll PJ. Use of RT-PCR to detect expression of neuropeptides and their receptors in lung cancer. Lung Cancer. 2001; 33:1-9.
33. Moody TW, Lee L, Ramos-Alvarez I, Jensen RT. Neurotensin receptors regulate transactivation of the EGFR and HER2 in a reactive oxygen species-dependent manner. Eur J Pharmacol 2019; 865: 17273.
34. Alifano M, Souaze F, Dupouy S, Camilleri-Broet S, Younes M, Ahmed-Zaid SM et al. Neurotensin receptor 1 determines the outcome of non-small cell lung cancer. Clin Cancer Res 2010; 16: 4401-4410.
35.Dupouy S, Viardot-Foucault V, Alifano M, Souaze F, Pul-Dureau G, Chaouat M et al. The neurotensin receptor-1 pathway contributes to human ductal breast cancer progression. PLoS One 2009. 4: e4223.
36. Thai AA, Solomon BJ, Sequist LV, Gainor JG, Heist RS. Lung Cancer. Lancet 2021; 398: 535-554.
37. Blobel CP. ADAMs: Key components in EGFR signaling and development. Nat Rev Mol Cell Biol 2005; 6: 32-43.
38. Wu P, Wee P, Jiang J, Chen X, Wang Z. Differential regulation of transcription factors by location-specific EGFR receptor signaling via a spatio-temporal interplay of ERK activation. PLoS One 2012; 7: e41354.
39. Brewer MR, Yun CH, Lai D, Lemmon MA, Eck MJ, Pao W. Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. Proc Natl Acad Sci USA 2013; 110: E3595-E3604.
40. Di Florio A, Sancho V, Moreno P, Delle Fave G, Jensen RT. Gastrointestinal hormones stimulate growth of foregut neuroendocrine tumors by transactivating the EGF receptor. Biochem Biophys Acta 2013; 1833: 573-82.
41. Muller KM, Tveteraas IH, Aasrum M, Odegard J, Dawood M, Dajani O et al. Role of protein kinase C and epidermal growth factor receptor signaling in growth stimulation by neurotensin in colon carcinoma cells. BMC Cancer 2011; 11: 421.
42. Zhou Z, Xie J, Cai Y, Yang S, Chen Y, Wu HR. The significance of NTR1 expression and its correlation with β-catenin and EGFR in gastric cancer. Diagn. Pathol 2015; 10: 173.
43. Wu Z, Galmiche A, Liu J, Stadler N, Wendum D, Segal-Bendirdjian E et al. Neurotensin regulation induces overexpression and activation of EGFR in HCC and restores response to erlotinib and sorafenib. Cancer Lett. 2017; 388: 73-84.
44. Heppner DE, van der Vliet A. Redox-dependent regulation of epidermal growth factor receptor signaling. Redox Biol 2016; 8: 24-27.
45. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2018; 68: 7-30.
46. Maximiano S, Magalhaes P, Guerreito MP, Morgado M. Trastuzumab in the treatment of breast cancer. Biodrugs 2016; 30:75-86.
47. Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 2013; 3: 224-237.
48. Doroshow JH, Juhasz A, Ge Y, Holbeck S, Lu J, Antony S et al. Antiproliferative mechanisms of action of the flavin dehydrogenase inhibits diphenylene iodonium and di-2-thienyliodonium based of molecular profiling on the NCI-60 human tumor cell panel. Biochem Pharmacol 2012; 83: 1195-1207.
49. Laskin J, Liu SV, Tolba K, Heining C, Schlenk RF, Cheema P et al. NRG1 fusion-driven tumors: Biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol 2020; Dec31:1693-1703.
50. Jung Y, Yong S, Kim P, Lee HY, Jung Y, Keum J et al. VAMP2-NRG1 Fusion Gene is a Novel Oncogenic Driver of Non-Small-Cell Lung Adenocarcinoma. J Thorac Oncol 2015; 10: 1107-1111.
51. Kiavue N, Cabel L, Melaabi S Bataillon G, Callens C, Lerebours F. et al. ERBB3 mutations in cancer: Biological aspects, prevalance and therapeutics. Oncogene 2020; 39: 487-502.
52. Ocana A, Vera-Badillo F, Seruga B, Templeton A, Pandiella A, Amir E. HER3 over-expression and survival in solid tumors: A Meta-analysis. JNCI 2013; 105:266-273.
53. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91; 231-241.
54. Moody TW, Ramos-Alvarez I, Jensen RT. Adding of neurotensin to non-small cell lung cancer cells increases tyrosine phosphorylation of HER3. Peptides 2022; 156: 170858.
55. Shimizu T, Yonesaka K, Hayashi H, Iwasa T, Haratani K, Yamada H et al. Phase 1 study of new formulation of patritumab (U3-1287) process 2, a fully human anti-HER3 monoclonal antibody in combination with erlotinib in Japanese patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol 2017; 79: 489-495.
56. Sequist LV, Gray JE, Harb WA, Lopex-Chavez A, Doebele RC, Modano MR et al. Randomized phase II trial of seribantumab in combination with erlotinib in patient with EGFR wild-type non-small cell lung cancer. Oncologist 2019; Aug 24: 1095-1102.