Neurokinin Receptor-1 Are Involved In The Study Of The Development Of Non-small Cell Lung Cancer And The Mechanisms Of EGFR Trans-activation

Lung cancer was the malignant disease type with the highest incidence and mortality worldwidely,divided into small-cell lung cancer(SCLC)and non-small-cell lung cancer(NSCLC)according to its tissue characteristics.Furthermore,the incidence of NSCLC is much higher than SCLC.The frequency of mutations in Epidermal Growth Factor Receptor(EGFR)is higher in NSCLC patients.Therefore,patients with active mutation of EGFR are often treated with EGFR tyrosine kinase inhibitors(EGFR-TKIs),but acquired resistance is prone to occur during EGFR-TKIs treatment,and the therapeutic effect of such drugs on wild-type EGFR is not effective.Therefore,platinum and paclitaxel are still the main treatment regimens in clinical therapy for the patients with wild-type EGFR or resitance to EGFR-TKIs,unfortunetly causing the large toxic side effects and limited overall survival time.Therefore,there is an urgent need to seek new therapeutic targets and treatment options to improve the therapeutic effect of NSCLC.G Protein-Coupled Receptor(GPCR)plays an important role incancer progression,such as tumor cell proliferation,migration,invasion,angiogenesis,drug resistance,and Epithelial-Mesenchymal Transition(EMT),so the research of antitumor drugs targeting GPCR is one of the emerging development directions in the field of drug development.Neurokinin-1 receptor(NK1R)as an important member of the GPCR family,is abnormally expressed in a variety of tumors featured with an important tumor growth factor.Clinical studies have shown that the upregulated expression of NK1 R is associated with poor prognosis in a variety of tumor such as glioma,breast cancer and pancreatic cancer.GPCR can involve in regulating the physiological processes such as proliferation,migration and chemotherapy drug resistance by transactivating EGFR in tumor cells.Our previous studies have shown that NK1 R is highly expressed in NSCLC cells that are not sensitive to EGFR-TKIs,and associated with tumor malignancy and poor prognosis.In NSCLC cells,NK1 R can regulate the proliferation and migration process with cross-talk of EGFR signaling pathway,and inhibition of NK1 R can block the growth of NSCLC cells in vivo and in vitro.However,it has not been clarified for the detailed mechanism of NK1 R and EGFR interaction in NSCLC for the further exploration of the involvement of NK1 R in regulating the process of EGFR-TKI NSCLC resistance.Our research constructed NSCLC cells model of acquired resistance for EGFRTKI.We found NK1 R was significantly upregulated in EGFR-TKIs acquired resistant NSCLC cells characterized epithelial mesenchymal transition.Aprepitant as a specific antagonist of NK1 R inhibited cell proliferation and migration of EGFR-TKIs resistant NSCLC cells.Aprepitant treatment reversed the EMT process showing the increase of the epithelial marker E-cadherin and the decrease of the mesenchymal marker vimentin.We found that inhibition of expression and activity of NK1 R increased the sensitivity of cisplatin and docetaxel to EGFR-TKIs primary resistant and acquired resistant NSCLC cells.Based on previous research,we further explored the mechanism of NK1 R transactivating EGFR.Western Blot experiments preliminarily showed NK1 R activates EGFR through MMPs-mediated ligand-dependence,and at the same time through co-immunoprecipitation(Co-IP)experiments proves that ternary complexes may be formed between NK1 R and EGFR through scaffold protein β-arrestins,and then mediate the trans-activation of EGFR in a nonligand-dependent manner.In summary,we found that antagonism of NK1 R improved the sensitivity of chemotherapy drugs to NSCLC cells.EGFR was trans-activted by NK1 R through MMP-mediated ligand-dependent and β-arrestins-mediated non-ligand-dependent pathway,which further provides experimental basis for NK1 R as a potential target for NSCLC therapy,and provides new treatment options and ideas for EGFR-TKIs insensitive NSCLC subtypes.