Abstract 1690: Myc suppression permits entry into the cancer endocycle to evade toxic effects of chemotherapy

Abstract Recent advances in precision medicine and immunotherapy have made great strides in cancer treatment and care, but chemoresistance remains a major challenge. One method of chemoresistance employed by cancer cells is accession of the protective polyaneuploid cancer cell (PACC) state, in which cells enter a functionally dormant state upon environmental stress. Entry into the PACC state begins with a whole-genome duplication event followed by endocycling, where the cells are metabolically active and cycling through repeated G1, S and G2 phases of the cell cycle without dividing. While in this state, cells avoid the mitotic stress exerted by common chemotherapeutics and survive therapy, eventually undergoing a depolyploidization process to repopulate the tumor, driving cancer lethality. The mechanisms by which a cancer cell can switch between a mitotic cell cycle and an endocycle are unknown. Cancer is characterized by deregulated cell proliferation, often driven by mutation or amplification of genes that govern the cell cycle. C-myc, an oncogenic transcription factor, is dysregulated in roughly 70% of cancers and is clinically used as a negative prognostic factor for disease-free survival and metastasis. C-myc is responsible for the transcriptional activation of many cell cycle-related genes, and repression of cell cycle inhibitors. Our data indicate that endocycling cells in the PACC state downregulate c-myc expression. Transcriptomic analyses show repression of myc targets, along with supporting protein data that total c-myc protein levels are decreased. While myc downregulation is expected in non-proliferative cells, the compensatory mechanisms mediating the G1/S transition in the cancer endocycle remain unknown. These observations suggest the presence of underlying mechanisms to reprogram the mitotic cell cycle to access the PACC state. We hypothesize that myc downregulation is essential for cells to activate the cancer endocyle and enter the protective PACC state. Understanding the mechanisms that govern this transition is crucial to generate next-generation cancer therapeutics to block accession or disrupt this state. Citation Format: Michael Loycano, Kenneth J. Pienta, Sarah R. Amend. Myc suppression permits entry into the cancer endocycle to evade toxic effects of chemotherapy [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 1690.