Co-inhibition of EGFR and IGF1R synergistically impacts therapeutically on adrenocortical carcinoma.
OBJECTIVE
Adrenocortical carcinoma (ACC) is a rare tumor with very poor prognosis and no effective treatment. The aim of this study was to explore a novel therapy co-targeting EGFR and IGF1R in vitro and vivo.


METHODS
The expression of EGFR and IGF1R were evaluated in a series of adrenocortical tumors by immunohistochemistry. Cell viability of ACC cell lines H295R and SW13 were determined by MTT assay after treatment with the combination of EGFR inhibitor Erlotinib and IGF1R inhibitor NVP-AEW541. Apoptosis was assessed by flow cytometry. The mechanism within intracellular signaling pathways was analyzed by Western blot. Mice bearing human ACC xenografts were treated with Erlotinib and NVP-AEW541, and the effects on tumour growth were assessed.


RESULTS
Our results show a significant over-expression of EGFR (66.67%) and IGF1R (80.0%) in ACC. Besides, the co-overexpression of EGFR and IGF1R was seen in 8/15 ACCs, as compared with ACAs (P<0.05). Erlotinib and NVP-AEW541 significantly inhibited cell viability and induced apoptosis by blocking phosphorylation of MEK/ERK and AKT, respectively. Meanwhile, we found that single inhibition of IGF1R induced compensatory activation of MEK/ERK, leading to sustained activation of mTOR, which represent as aggregation of EGFR and IGF1R downstream components. More importantly, the combination of Erlotinib and NVP-AEW541 enhances anti-tumour efficacy compared to treatment with either agent alone or to untreated control in vitro and vivo.


CONCLUSIONS
In conclusion, coinhibition therapy targeting EGFR and IGF1R may be considerable for treatment of ACC in the future.
Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Lieyu
L
Xu
Department of Endocrinology, Clinical Center of Shanghai Endocrine and Metabolic Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Yicheng
Y
Qi
Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.|Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Yunze
Y
Xu
Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Jianpo
J
Lian
Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Xiaojing
X
Wang
Department of Endocrinology, Clinical Center of Shanghai Endocrine and Metabolic Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Guang
G
Ning
Department of Endocrinology, Clinical Center of Shanghai Endocrine and Metabolic Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Weiqing
W
Wang
Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Yu
Y
Zhu
D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1
EGFR; IGF1R; adrenocortical carcinoma; coinhibition therapy; crosstalk