Oncotarget

Research Papers:

Co-inhibition of EGFR and IGF1R synergistically impacts therapeutically on adrenocortical carcinoma

Lieyu Xu _, Yicheng Qi, Yunze Xu, Jianpo Lian, Xiaojing Wang, Guang Ning, Weiqing Wang and Yu Zhu

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Oncotarget. 2016; 7:36235-36246. https://doi.org/10.18632/oncotarget.8827

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Abstract

Lieyu Xu1,*, Yicheng Qi2,*, Yunze Xu1,3,*, Jianpo Lian1, Xiaojing Wang1, Guang Ning2, Weiqing Wang2, Yu Zhu1

1Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

2Department of Endocrinology, Clinical Center of Shanghai Endocrine and Metabolic Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

3Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

*These authors contributed equally and shared the first authorship

Correspondence to:

Yu Zhu, email: [email protected]

Keywords: adrenocortical carcinoma, EGFR, IGF1R, coinhibition therapy, crosstalk

Received: November 22, 2015    Accepted: March 29, 2016    Published: April 18, 2016

ABSTRACT

Purpose: 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.


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