Abstract B037: Characterizing and targeting polyaneuploid/polyploid giant cancer cells (PACCs/PGCCs)

Abstract

Abstract Polyaneuploid/polyploid giant cancer cells (PACCs/PGCCs) 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 PACCs/PGCCs 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. 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 anti-cancer agents including taxanes, vinca alkaloids and platinum-based chemotherapies. 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 were not yet known. PACCs/PGCCs can repopulate in vitro as they generate tumors when inoculated into mice. Their daughter cells acquire a mesenchymal phenotype, which is a key transformation for cancer development, progression and metastasis. Emerging evidence has demonstrated PACCs/PGCCs arise in lung cancer, cervical carcinoma, ovarian cancer, prostate cancer, glioblastoma, colorectal cancer and breast cancer. Therefore, revealing the molecular events that cause PACCs/PGCCs to form could lead to clinically relevant approaches for treating recurrent and metastatic disease. With our studies, we discovered that Aurora kinases and Cyclin-dependent kinases 4/6 (CDK4/6) were two separate synergistic determinants of distinct switches from the proliferative cell cycle to polyploid growth state in lung cancer cell lines. When Aurora kinases are inhibited together, cancer cells uniformly grow into multinucleated PACCs/PGCCs whereas inactivation of CDK4/6 forms mononucleated PACCs/PGCCs. These cells adopt an endoreplication in which the genome replicates, mitosis is omitted and cells grow in size. Consequently, such cells continue to safely grow in the presence of anti-cancer agents. These PGCCs can reenter the proliferative cell cycle and grow in cell number when the treatment is terminated. Based upon our results, we were funded to find chemical inhibitors to target PACCs/PGCCs. We have conducted a high-throughput screen of 332,500 chemicals of the UT Southwestern chemical library to identify those that were toxic to our representative cell line model, but not to cells with normal ploidy, including immortalized normal human bronchial epithelial cells (HBECs). Currently, in our research program, we have two major projects, which includes: (1) A complete biological and mechanistic characterization of PACCs/PGCCs in cancer initiation, progression, metastasis and drug resistance, and (2) development of inhibitors to target PACCs/PGCCs as drug candidates for cancer therapies. To the best of our knowledge, ours are the first studies to describe the responsible genes involved in the formation of PACCs/PGCCs. Citation Format: Vural Tagal, Uttam K. Tambar, Michael G. Roth, John D. Minna. Characterizing and targeting polyaneuploid/polyploid giant cancer cells (PACCs/PGCCs) [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B037.