Abstract 1296: Targeting nuclear AURKA and hypoxia signaling pathway attenuates metastatic burden in triple negative breast cancer

Abstract

Abstract Despite remarkable progress in diagnosis and treatment, metastasis from the primary tumor to distant organs is responsible for over 90% of cancer deaths. Therefore, there is a need to understand the drivers of the process to detect, target, and develop therapeutics to treat metastases better and extend their lifespan. Aurora-A Kinase (AURKA) is a serine/threonine kinase that typically localizes in the cytoplasm. However, the nuclear localization of AURKA (N-AURKA) has been reported in multiple cancers and correlates with poor survival and the advanced/metastatic stage of the disease. AURKA is often present in the nucleus of metastatic Triple Negative Breast Cancer (TNBC) cells and patient biopsies compared to non-metastatic cells. Moreover, induced translocation of AURKA to the nucleus in experimental models of TNBC results in a 5-fold increase in metastases to the bones, lungs, and liver compared to AURKA in the cytoplasm. We have previously shown that N-AURKA under normoxic conditions binds to HIF1A/1B and leads to induction of hypoxia signaling via transactivation of Hypoxia Inducible Factors (HIFs)-dependent genes, including migration/invasion, survival/death, and stemness, promoting early cancer dissemination. Transactivation of HIF1-genes requires cofactor p300/CBP. It is currently unknown if N-AURKA/HIF1 transcription is p300 dependent. In this study, we used the small molecular inhibitor Chetomin to disrupt the interaction of HIF1A and co-activator CBP/p300 in experimental TNBC and animal models combined with AURKA inhibitor Alisertib. Disruption of the hypoxia signaling pathway significantly decreases the transactivation of HIF-dependent genes, including migration/invasion, survival/death, and stemness in N-AURKA cells. Moreover, in mouse models, inhibition of HIF1 activity via treatment with Chetomin in combination with AURKA inhibitor Alisertib significantly decreased metastatic burden suggesting that p300 binding to AURKA/HIF complex is critical for gene expression and enabling metastatic dissemination/colonization. Our studies show the mechanistic relationship between N-AURKA and hypoxia signaling and lay the foundation for developing novel combination treatment strategies to improve patient outcomes. Citation Format: Abha Maskey, Kristina Marinak Whately, Elena N. Pugacheva. Targeting nuclear AURKA and hypoxia signaling pathway attenuates metastatic burden in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1296.