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

Abstract

Alterations in the signaling pathways of epidermal growth factor receptors (HERs) are associated with tumor aggressiveness. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 60% of lung cancers. In a previous clinical study, NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in a selected population of stage I lung adenocarcinomas treated by surgery alone. In a second study, shown here, the frequent and high expression of NTSR1 was correlated with a pejorative prognosis in 389 patients with stage I to III lung adenocarcinoma, and was an independent prognosis marker.Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here we highlight the cellular mechanisms activated by Neurotensin (NTS) and its high affinity receptor (NTSR1) contributing to lung cancer cell aggressiveness. We show that the NTS autocrine and/or paracrine regulation causes EGFR, HER2, and HER3 over-expression and activation in lung tumor cells. The EGFR and HER3 autocrine activation is mediated by MMP1 activation and EGF “like” ligands (HB-EGF, Neuregulin 1) release. By establishing autocrine and/or paracrine NTS regulation, we show that tumor growth is modulated according to NTS expression, with a low growth rate in those tumors that do not express NTS. Accordingly, xenografted tumors expressing NTS and NTSR1 showed a positive response to erlotinib, whereas tumors void of NTSR1 expression had no detectable response. This is consistent with the presence of a NTS autocrine loop, leading to the sustained activation of EGFR and responsible for cancer aggressiveness.We propose the use of NTS/NTSR1 tumor expression, as a biomarker for the use of EGFR tyrosine kinase inhibitors in patients lacking EGFR mutation.

Neurotensin regulation induces overexpression and activation of EGFR in HCC and restores response to erlotinib and sorafenib

“…Western blots were processed as previously described [33]. Western blots were revealed with antibodies directed against EGFR, ERK1/2, Thr202/Tyr204 pERK, PKB, Ser473 p-PKB (Cell Signalling Technology ® ), Tyr1173 p-EGFR, actin (Santa Cruz Biotechnology ® ).…”

“…In addition, it was shown that the sustained stimulation Abbreviation: NTS, neurotensin; NTSR1, neurotensin receptor 1; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signalregulated kinases; PKB, protein kinase B; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; RT-PCR, reverse transcriptase-polymerase reaction; OS, overall survival. 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 of NTSR1 generated autocrine regulation of epidermal growth factor receptors, producing cell hyper-sensitivity to tyrosine kinase inhibitors, as is the case for erlotinib in lung cancer or lapatinib in breast cancer [6,33]. NTS is expressed in the fetal human liver but repressed in the normal adult liver.…”

NTSR1 (neurotensin receptor 1 (high affinity))

“…The recruitment of G protein was described through NTSR1 activation in microdomains (Heakal et al, 2011). In other cell types, cell proliferation, migration and invasion are depending on a transactivation of EGFR by NTSR1 (Amorino et al, 2007;Moody et al, 2014 ) or act through the increase of expression and activation of EGFR, HER2, HER3 (Younes et al, 2014;Dupouy et al, 2014).…”

“…Its functions in oncogenesis depend on EGFR, HER2 and HER3 expression in breast cancer cells (Dupouy et al, 2014).…”

“…Its activation enhances HER2, HER3 and EGFR expression in lung cancer (Younes et al, 2014). Pharmacological NTSR1 inhibitor (SR48692) inhibits EGFR activation (Moody et al, 2014).…”