Abstract 1572: Antiproliferative activity of enzalutamide and alisertib in prostate cancer cells overexpressing HMGA2

Abstract

Abstract Prostate cancer is one of the common types of cancer and remains the second leading cause of cancer-related deaths in men in the United States. High Mobility Group Protein AT-hook 2 (HMGA2), a DNA binding protein acts as a transcriptional regulating factor in gene transcription and facilitates epithelial-mesenchymal transition (EMT), which is usually the onset of prostate cancer progression and metastasis. HMGA2 isoforms include wild-type or full length that induces EMT, while the truncated isoform is associated with elevated proliferation and migration. Enzalutamide is a second-generation antiandrogen drug known to inhibit androgen receptor (AR) translocation into the nucleus by competitively binding AR and preventing androgen binding. Alisertib (MLN8237) is a small molecule inhibitor of Aurora kinase A has been utilized in clinical trials for neuroendocrine cancers and can also inhibit EMT. We aim to investigate which of the two drugs is effective in reducing proliferation in prostate cells overexpressing HMGA2 isoforms (wild-type and truncated). In this study, we treated LNCaP cells overexpressing HMGA2 with enzalutamide (1-30 µM) and alisertib (2.5-40 µM). Treatment with enzalutamide and alisertib indicated a dose-dependent decrease in cell proliferation with optimal dose at 20 µM for both drugs. LNCaP cells (LNCaP Neo) expressing low level of HMGA2 were observed to respond better to enzalutamide treatment, while those overexpressing HMGA2 (WT and TR) respond better to alisertib treatment. Interestingly, treatment with 20 µM enzalutamide and alisertib followed by Western blot indicated enzalutamide to have no effects on protein expression of HMGA2 isoforms, but greatly decreased the expression of AR in LNCaP cell overexpressing truncated HMGA2. On the other hand, alisertib increased the expression of wild-type HMGA2 whilst having no effects on protein expression of AR. Both drugs at 20 µM did not have any significant effect on the expression of EMT markers (snail and vimentin).In conclusion, alisertib is more potent than enzalutamide in decreasing cell proliferation in prostate cancer cells expressing HMGA2. Further studies need to be conducted to understand the role of HMGA2 in promoting resistance to enzalutamide and whether alisertib may be a better drug for patients that express HMGA2. Acknowledgements: These studies were supported by NIH/NIMHD 2U54MD007590 and 5U54MD013376-8281. Citation Format: Yusuf Mansur Liadi, Valerie Odero-Marah. Antiproliferative activity of enzalutamide and alisertib in prostate cancer cells overexpressing HMGA2 [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 1572.