Abstract 513: The link between polyploidy and replication stress in melanoma

Abstract

Abstract Genomic instability is a hallmark of cancer implicated in tumor evolution and resistance to therapy. However, the molecular mechanisms that underlie genomic instability are still poorly understood. One common feature of cancer cells is an elevated genomic content (polyploidy) which is also associated with the acquisition of therapy resistance. Here we demonstrate a link between genomic instability and polyploidization in melanoma cells. We show that polyploidy induced by treatment with small molecule inhibitors of various mitotic kinases, such as AURKA, AURKB and PLK1, leads to DNA damage in cells with elevated (>4n) DNA content. This DNA damage results from replication stress exacerbated by limited activation of p53 in malignant melanocytes. Pharmacological induction of p53 in polyploid cells using an MDM2 antagonist reduced DNA damage by blocking re-replication of the polyploid genome as a result of p53-mediated p21 activation and transactivation of DNA repair genes. Notably we found that p21 blockade using siRNA knockdown or genetic knockout shifted polypoid cell response to p53 activation from cytostatic to cytotoxic. As a result, p21-deficient cells exhibited enhanced sensitivity to mitotic blockade combined with p53 induction. Furthermore, TCGA dataset analysis showed poor progression free survival in melanoma patients with high p21 protein expression. These data argue for administering mitotic inhibitors and MDM2 antagonists, which are currently in clinical development, in conjunction with agents that target p21. In summary, our data here reveal that polyploidization can be a mechanism for induction of DNA damage and genomic instability associated with drug resistance in cancer and suggest a novel strategy for targeting these pathways to improve melanoma therapy. Citation Format: Anna E. Vilgelm, C. Andrew Johnson, Kiran Malikayil, Dayanidhi Raman, David Flaherty, Brian Higgins, Ann Richmond. The link between polyploidy and replication stress in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 513. doi:10.1158/1538-7445.AM2017-513