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Tumor Treating Fields (TTFields) can prolong survival of patients with glioblastoma (GBM), but GBM cells still escape this therapy requiring an urgent need for new or adjunct treatments. Recently we reported that TTFields disrupt primary cilia on GBM cells which lowers resistance to standard of care temozolomide chemotherapy. Here we asked if concomitant or sequential treatment of TTFields with other agents that interfere with GBM ciliogenesis enhance TTFields efficacy. Aurora Kinase A (AURKA) plays both a role in promoting cilia disassembly and regulating GBM growth in xenograft models. We found that within 24hr of treatment with the AURKA inhibitor, Alisertib, there was surprising and significant decrease in GBM cilia frequency across multiple GBM patient derived lines. However, similar Alisertib treatment did not affect neuronal or glial cilia frequencies in mixed primary cell cultures from mouse forebrain. Notably, overnight treatment of patient GBM biopsy ex vivo with Alisertib also resulted in reduced cilia frequency within the tumor tissue. Next, we co- or sequentially treated several different GBM patient cell lines with 24hr of 200kHz TTFields together with or followed by 250nM or 1µM Alisertib and examined the subsequent expansion of cells in vitro. We observed a significant synergistic reduction in cell proliferation compared to either treatment alone. However, this synergistic effect does not appear to be cilia-dependent as dual treatment reduction in proliferation was still observed in cell lines lacking different key cilia genes or in GBM cells that naturally lack cilia. Considering Alisertib crosses the blood brain barrier and inhibits intracranial growth of tumors, our data warrant investigation of whether concomitant or sequential treatment of TTFields and Alisertib in vivo can further prolong survival. Citation Format: Jia Tian, Julianne Mallinger, Ping Shi, Dahao Ling, Loic Deleyrolle, Min Lin, Habibeh Khoshbouei, Matthew Sarkisian. Inhibition of AURKA destabilizes glioblastoma primary cilia and sensitizes cells to tumor treating fields (TTFields) in vitro and ex vivo [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 5961. |
