Abstract 375: Cancer cells may utilize centrosome amplification to promote survival as a response to chemotherapeutic stress

Abstract Therapy resistance is one of the most common underlying causes of poor prognosis in cancer patients, ultimately driving fatal outcome. We have previously demonstrated that following chemotherapeutic stress, a subset of cancer cells undergo a mitotic skip and enter an endocycle, causing whole-genome duplication without division. This endocycling cell state is resistant to cytotoxic therapies and thus is an actuator of therapy resistance. Cells in the endocycling state eventually undergo depolyploidization and repopulate the tumor, observed clinically as a recurrence. A common feature of cancers is centrosome amplification (CA) that includes aberrations in centrosome number (>2 centrosomes/cell), size, shape, and/or positioning. Our preliminary data has shown that endocycling cancer cells exhibit CA following treatment across multiple types of chemotherapies. Based upon this data, we hypothesize that studying centrosome dynamics and abnormalities presents a window into better understanding endocycle biology and this novel mechanism of therapy resistance.We have found that the population of prostate cancer and breast cancer cells possessing CA following treatment with LD50 dose of cisplatin or docetaxel increased as a function of recovery time to over 95% by day 10, with nearly all cells clustering extra centrosomes together. Of note, the number of mitotic skips an endocycling cell undergoes has not been found to be associated with the number of centrosomes the cell has. PLK4 is a kinase essential for centriole duplication and its overexpression causes CA. Immunofluorescence analysis has revealed that endocycling cancer cells exhibit an increase in PLK4 protein expression. Endocycling cancer cells also exhibit increased protein expression of KIFC1, a mediator of centrosome clustering. Both PLK4 and KIFC1 protein expression have been found to positively correlate with DNA content. We hypothesize that endocycling cells may use clustered, supernumerary centrosomes as platforms to locally concentrate signaling molecules, lowering the activation threshold for downstream effectors. Published data from bioID proteomics of centrosomal proteins has revealed an enormous unexplored protein landscape around these organelles. Because of this, CA may be a critical mechanism for endocycling cancer cells to survive and maintain this resistant cell state. Citation Format: Madison M. Purkerson, Sarah R. Amend, Kenneth J. Pienta. Cancer cells may utilize centrosome amplification to promote survival as a response to chemotherapeutic stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 375.