Study of pathways involved in Aurora kinases signaling and mechanisms of action of the inhibitor AMG 900 in adrenocortical tumor

Abstract

Adrenocarcinomas are tumors with low incidence between all types of tumors. However, a mutation in the TP53 gene, commonly found in Southern Brazil, increases the predisposition to the disease. There are no effective therapies for advanced stage adrenocarcinomas, which leads to a low survival index for patients with stage IV tumors. Therefore, the discovery of new therapeutic targets is of fundamental importance to design effective drugs for adrenal carcinoma treatment. Recently, it has been described by our group that Aurora kinases expression is frequently increased in tumors with advanced clinic stages, suggesting that the expression of these proteins might be strongly associated with tumorigenesis. The AMG 900, a potent and highly selective Aurora kinase pan-inhibitor, is orally bioavailable and active in cell lineages that are resistant to multiple drugs, being able to potentiate the antiproliferative effects of paclitaxel and to decrease the proliferation of different breast cancer and myeloid leukemia cell lineages. At the moment, the AMG 900 is in phase I clinical trial in patients with advanced tumors. Studies performed by our laboratory showed that the inhibition of Aurora kinases after treatment of adrenocarcinoma cell lineage with the AMG 900, decreases cell proliferation and hormone synthesis. Thus, the aim of this study is to search for pathways involved in the signaling of Aurora kinases and the putative mechanisms of action of the inhibitor AMG 900 that are still not described in the literature. We intend to analyze the differences in the protein content of two adrenal carcinoma cell lineages, NCI-H295R and SW13, after treatment with the Aurora kinase inhibitor, AMG 900, through proteomic strategies. For the proteomics validation, it will be selected proteins that are related to hormone synthesis and tumor development. After the selected targets validation, the coding genes of the proteins validated will be silenced by siRNA and these targets will be driven to a second phase of screening which will be performed functional assays as migration, cell proliferation, apoptosis and hormone synthesis to clarify the role of these targets in adrenocarcinoma development and progression. The data obtained will allow us understand pathways involved in Aurora kinase signaling and the putative mechanisms of action of the inhibitor AMG 900 that are not yet described in the literature, contributing to the rational design of new drugs that could act individually or in combination with the AMG 900.