Abstract 1795: Molecular vulnerabilities of the polyaneuploid cancer cell state

Abstract Once cancer has metastasized it remains incurable owing to resistance to nearly all systemic therapies. Classical views of therapeutic resistance include tumor heterogeneity and genetic instability, but our group and others have identified an unappreciated cancer cell phenotype, the polyaneuploid cancer cell (PACC) state, that provides an alternative model. The PACC state is induced upon exposure to a variety of applied stressors, including multiple different classes of chemotherapy, and is characterized by an enlarged cell size, polyploidy of the typically aneuploid cancer genome, and the ability to repopulate tissue through depolyploidization. We have demonstrated that PACCs are present in a variety of cell lines, arise in response to a multitude of stressors in vitro, and are resistant to cisplatin, docetaxel and Ipatasertib treatment. Thus, we hypothesize that the PACC state is driving cancer’s therapeutic resistance to nearly all available treatment regimens and enabling cancer relapse. Elimination of the PACC state is essential to prevent cancer recurrence, and ultimately enable a cure for cancer.To identify candidate drug targets specific to the PACC state, we performed RNA sequencing, NanoString mRNA panels, bulk proteomics and cell surface proteomics of PACCs versus their parental cell line. PACCs were induced from prostate cancer lines PC3 and LNCaP, and breast cancer line MDAMB231 with both cisplatin and docetaxel treatment. Initial datasets with PC3 cells found that 1013 genes are enriched (greater than 1.5 Log2 Fold Change) in cisplatin induced PACCs while 88 genes are enriched in docetaxel induced PACCs. 22 genes were enriched with both chemotherapy treatments implying that there are genes common to the PACC state. NanoString mRNA and proteomic analysis further validated a subset of the overlapping genes, including ATF3, BIRC3, IL6, and NOX5.Our existing data reveals that there are molecular vulnerabilities of the PACC state that can be manipulated for therapeutic elimination. We will further validate candidate genes across numerous stressors and cell lines and then assess the PACC state’s dependence on these pathways through inhibition and engineered cell lines. Information from these studies will directly lead to development of a therapeutic strategy specifically targeting the PACC state, with the intention of eliminating cancer resistance. Citation Format: Luke Loftus. Molecular vulnerabilities of the polyaneuploid cancer cell state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1795.