The Study On Molecular Mechanism Of Dual Inhibition On EGFR And IGF1R For Treatment Of Adrenocortical Carcinoma

Purpose Adrenocortical carcinoma is a rare neoplasm with poor prognosis,and previous therapies have been proven to be limited efficient.Therefore,we aimed at exploring novel therapy co-targeting EGFR and IGF1 R in vitro and vivo in this study.Methods The EGFR,IGF1 R,p-m TOR and p-ERK proteins were evaluated in 37 adrenocortical tumors by IHC.Effects of inhibitor on viability and apoptosis of SW13 and H295 R cells were studied by MTT and Annexin-V/PI assay.The mechanism within intracellular signaling pathways was analyzed by Western blot.In vivo assay was further investigated by xenograft mouse model.Results We found significant overexpression of EGFR(75.0%),IGF1R(70.0%),p-m TOR(70.0%)and p-ERK(60.0%)in ACC,also co-overexpression of EGFR and IGF1 R in 12/20 ACC,as compared with ACA(P<0.05).Erlotinib and NVP-AEW541 could inhibit cell viability and induce apoptosis by blocking phosphorylation of MEK/ERK and AKT,respectively.Meanwhile,we found the crosstalk between EGFR and IGF1 R,in which single inhibition of IGF1 R induced compensatory activation of MEK/ERK,leading to sustained activation of m TOR.We found m TOR represent as aggregation of EGFR and IGF1 R downstream signaling pathways.More importantly,co-targeting therapy could synergistically inhibit cell viability of SW13(CI: 0.58±0.23)and H295 R cells(CI: 0.20±0.05),induce apoptosis and inhibit tumor xenograft growth by dual suppression of MEK/ERK and AKT/m TOR pathways.Conclusions Our results substantiated the role of EGFR,IGF1 R and their downstream pathways in the tumorigenesis of ACC.We found the crosstalk between EGFR and IGF1 R pathways,and further demonstrated that m TOR represent as aggregation of downstream components.From this study,we could draw the conclusion that coinhibition therapy targeting EGFR and IGF1 R may be considerable for treatment of ACC in the future.