Abstract PO-128: Lack of Aurora kinase signaling leads cancer cells to adopt an endocycle and form polyploid multinucleated giant cells that resist antimitotic drugs

Polyploid multinucleated (PP/MN) giant cancer cells are common in tumors and have been tightly linked with tumor heterogeneity, resistance to cancer therapy, tumor relapse, metastasis, malignancy, immunosuppression, modulation of the tumor microenvironment and cancer stem cells. The abundance of PP/MN cancer cells is markedly higher in high-grade malignant tumors than in low-grade tumors, in the metastatic foci than in the primary tumor, and in relapsing tumors post-chemotherapy than in tumors before therapy. They can remain viable and metabolically active for extended periods of time. They can secrete an array of growth factors, cytokines and chemokines. Immunosuppressive proteins including programmed death-ligand 1 (PD-L1) were also found to be overexpressed in these cells. Such cells are known to escape from cytotoxicity induced by major antimitotic agents including taxanes and vinca alkaloids. Therefore, they are responsible of contributing to a microenvironment advantageous for tumor growth and survival. However, the molecular mechanisms that cause these cells to form are yet known. PP/MN cancer cells can repopulate, and form macroscopic colonies and spheroids in vitro as they generate tumors when inoculated into mice. In comparison to diploid cancer cells, these daughter cells lower the expression of epithelial markers and acquire a mesenchymal phenotype, which is a key transformation for cancer development, progression and metastasis. Emerging evidence has demonstrated that PP/MN cancer cells arise in lung cancer, cervical carcinoma, ovarian cancer, prostate cancer, glioblastoma, colorectal cancer, and breast cancer. The role of PP/MN giant cancer cells in cancer is well documented. Therefore, revealing the molecular events that cause PP/MN giant cells to form can lead to clinically relevant approaches for treating recurrent and metastatic disease, which remains a major global health issue despite decades of substantial research. In this study, we discover that Aurora kinases are synergistic determinants of a switch from the proliferative cell cycle to polyploid growth and multinucleation in lung cancer cell lines. When Aurora kinases are inhibited together, lung cancer cells uniformly grow into PP/MN giant cells. These cells have adopted an endocycle in which the genome replicates, mitosis is omitted and cells grow in size. Consequently, such cells continue to safely grow in the presence of antimitotic agents. These polyploid multinucleated cancer cells can re-enter the proliferative cell cycle and grow in cell number when the treatment is terminated. We also demonstrate that chemical programming of the cells to endocycle with Aurora kinase inhibitors can serve as a methodology to identify antimitotic agents in a simple, high-throughput fashion. To the best of our knowledge, ours is the first study to describe the responsible genes involved in the formation of PP/MN giant cancer cells. Citation Format: Vural Tagal, Michael G. Roth. Lack of Aurora kinase signaling leads cancer cells to adopt an endocycle and form polyploid multinucleated giant cells that resist antimitotic drugs [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-128.