Blockade Of Beta-Catenin Pathway Combined With Aurora Kinase Activity Inhibition Enhances Antitumor Effects In Adrenocortical Cancer Cells.

Abstract Adrenocortical cancer (ACC) is a rare and aggressive type of endocrine tumor with high risk of recurrence and metastasis. The overall survival of patients diagnosed with ACC is very low and current treatment for metastatic stages remain limited to mitotane, which has low efficiency in advanced stages of the disease and is associated with high toxicity and side effects. Therefore, identification of new biological targets to improve ACC treatment is crucial. Beta-catenin alterations have been found in approximately 30% of ACCs and blockade of Wnt-beta-catenin showed to decrease adrenal steroidogenesis and increase apoptosis of ACC cells, NCI-H295, in vitro and in a mouse model. Aurora kinases are known to play an important role in cell division during G1-M phase and their aberrant expression is correlated with poor prognosis in different types of tumors. Hence, we hypothesized that inhibition of aurora kinase activity combined with beta-catenin pathway blockade could promote better antitumor effects in NCI-H295 cells. We studied the in vitro effects of AMG 900, an aurora kinase activity inhibitor and PNU-74654, a beta-catenin pathway blocker, in proliferation, migration, colony establishment and invasion of NCI-H295 and SW-13 ACC cell lines. Our results show that the combination of AMG 900 with PNU-74654, decreases cell proliferation and viability, compared to either one of the single treatments. Regarding cell invasion and clonogenesis inhibition, AMG 900 was more efficient than PNU-74654, and its combination with the latter did not improve these effects. On the other hand, PNU-74654 was more effective in decreasing cortisol secretion. Taken together, our data suggest that inhibition of aurora kinases activity combined with blockade of the beta-catenin pathway could bring new approaches for designing new drugs to treat certain ACCs. Citation Format: Andrea G. Maria, Kleiton S. Borges, Regia C. Lira, Carolina H. Thome, Annabel Berthon, Ludivine Drougat, Fabio R. Faucz, Vitor M. Faca, Luiz G. Tone, Constantine A. Stratakis. Blockade of beta-catenin pathway combined with Aurora kinase activity inhibition enhances antitumor effects in adrenocortical cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 412.