Abstract
PurposeAdrenocortical 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.MethodsThe 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.ResultsOur 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.ConclusionsIn conclusion, coinhibition therapy targeting EGFR and IGF1R may be considerable for treatment of ACC in the future.
Highlights
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, with annual prevalence of only 0.5 to 2 cases per million people [1]
We found that single inhibition of Insulin-like growth factor 1 receptor (IGF1R) induced compensatory activation of MEK/ERK, leading to sustained activation of mTOR, which represent as aggregation of epidermal growth factor receptor (EGFR) and IGF1R downstream components
In conclusion, coinhibition therapy targeting EGFR and IGF1R may be considerable for treatment of ACC in the future
Summary
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, with annual prevalence of only 0.5 to 2 cases per million people [1] It is extremely aggressive and nearly half newly diagnosed are advanced diseases, whose 5-year survival rate is often less than 15%. It has been demonstrated that IGF1R inhibitors could inhibit proliferation and promote apoptosis, even with alleviation of mitotane-associated cytotoxicity in ACC cell lines [6, 9]. Clinical trials targeting IGF1R, such as IMC-A12, OSI-906 and figitumumab, all showed comparatively poor efficiency [10,11,12] All these results demonstrated that single inhibition of IGF1R is not sufficient to improve overall survival, owning to heterogeneity of ACC, and led our insight into alternative combination therapy
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