Targeting RET Sensitizes Oral Squamous Cell Carcinoma To EGFR Inhibitor Erlotinib

Background and aim:Aberrant activation of transmembrane receptor tyrosine kinase(RTK)signaling is commonly observed in multiple malignancies and contributes to tumor progression.Targeting RTKs with antibodies or small molecular inhibitors is a validated therapeutic approach used cancer treatment.Here we demonstrate that elevated level of a RTK,rearranged during transfection(RET),was found in oral squamous cell carcinoma(OSCC),and we also found novel mechanism to improve efficacy of EGFR inhibitor elortinib on OSCCMethods:Information regarding RET gene status was investigated via the TCGA.RET expression levels in OSCC were examined in 8 fresh tumor samples and paired negative resection margins by western blot.Immunohistochemistry was used to evaluate RET level in 145 OSCC samples,and the prognostic value of RET was analyzed.The role of RET in OSCC was further investigated by in vitro and in vivo assays.Moreover,the interaction between RET and EGFR signaling was analyzed by knockdown RET or EGFR respectively The clinical value of the interaction between RET and EGFR was further valued in OSCC clinical samples by immunohistochemistry staining of RET and p-EGFR.Moreover,the role of RET in OSCC sensitivity to erlotinib was investigated by RET knockdown to determine erlotinib IC50 contrition,and the efficacy of the combination of RET inhibitor regorafenib and erlotinib was valued by in vitro and in vivo assaysResults:The elevated levels of RET are observed in OSCC and that high levels of RET correlate with increased tumor size,advanced tumor stage and decreased overall survival rate In addition,the OSCC cell proliferation and invasion was inhibited by RET knockdown in vitro and in vivo.Moreover,the inhibition of RET expression markedly reduced EGFR phosphorylation and downstream EGFR signaling,The staining percentage value of RET and p-EGFR was also positively correlated in OSCC tissues.The inhibition of RET signaling significantly increased the sensitivity of OSCC cells to the EGFR inhibitor erlotinib in both in vitro and in vivo models.Conclusion:Our results offer a preclinical proof-of-concept supporting a role for RET signaling inhibition in a targeted therapeutic approach to improve the efficacy of EGFR inhibition in HNSCC.