Abstract 1242: Induction and targeting of polyploid senescent cells in cancer therapeutics

Abstract Therapy-induced cellular senescence (TCS), an emerging concept in cancer therapeutics, describes an in vivo response of human tumors to chemotherapy and radiation. These treatments elicit a coordinated response that results in prolonged cell cycle arrest, characteristic senescence morphology and expression of senescence-specific markers. In the past decade, a growing body of evidence has supported the hypothesis that “senescence response occurs in treated human cancers and the response is reversible.” We now present evidence that TCS may be adverse to cancer therapeutics based on a clinicopatholgical study conducted in patients with advanced non-small cell lung cancer following induction therapy prior to surgery. To further define how a subpopulation of senescent cells could escape terminal arrest, our work now implicates a polyploid state through which senescent cells can survive and eventually resume proliferation. In H1299 lung cancer cells, we show that mitotic kinase Cdk1 facilitates endoreplication and formation of polyplid senescent cells (PSCs) following chemotherapy as the genetic modulation of Cdk1 activity profoundly affect the prevalence of these polyploid cells. Importantly, senescence escape occurs from the PSCs at 2.5 times the frequency of escape observed from diploid (2/4n) cells through novel non-canonical cell division mechanisms. Furthermore, we also demonstrate distinct functions of p21 and p27, two members of KIP family in TCS. While both interact with endogenous cyclin B1-Cdk1 complex in senescent cells, only p27 directly inhibits Cdk1 kinase activity and modulates PSC formation, whereas the knockdown of p21 leads to massive apoptosis. Finally, we show that statins, HMG-CoA inhibitors, currently approved for treatment of dyslipidemia down-regulate several key targets of the Cdk1 pathway, including Cdk1 itself, cyclin B1, and survivin, while up-regulating p27. Statins both decrease polyploid cells and abrogate escape of several cancer cell lines from TCS. Altogether, our work here challenges the current cancer treatment paradigm and supports the incorporation of novel strategies to enforce irreversible cell cycle exit in senescent tumor cells following treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1242. doi:10.1158/1538-7445.AM2011-1242