Abstract
Abstract
Senescence represents a fundamental response to cancer therapy. Accumulating senescent cells contribute to the deleterious outcomes of cancer therapy including cancer relapse, effects that may be largely mediated by the Senescence-Associated Secretory Phenotype (SASP). In this work, we show that tumor cells induced into senescence by etoposide retain proliferative capacity based on their capacity to generate proliferating colonies in culture as well as giving rise to viable tumors in vivo. Using a flow cytometry-based enrichment approach based on enlarged size and expression of Senescence-Associated β-galactosidase (SA-β-gal), we were able to utilize real time imaging to establish the re-emergence of non-small cell lung cancer cells from senescence-based arrest and the generation or proliferating daughter cells (i.e. self-renewal). Moreover, we implemented High-Speed Live-Cell Interferometry (HSLCI) to provide a single-cell lineage tracking of dividing senescent cells. The recovery from senescence was accompanied by resolution of several senescence-associated hallmarks, specifically SA-β-gal activity, p21Waf1/Cip1 and several components of the SASP (IL-1β, IL-6 and CXCL1). Our data suggests that Therapy-Induced Senescence (TIS) may ultimately be a transient process in that at least a subpopulation of tumor cells can recover proliferative capacity. We further demonstrate that the senolytic agent, ABT263, which has been shown to eliminate senescent cells from aging-related animal models can also eliminate senescent tumor cells that persistent after exposure to chemotherapy by shifting the response towards apoptotic cell death. Furthermore, sequential administration of ABT263 interferes with the ability of tumor cells induced into senescence by chemotherapy to recover growth potential. These studies suggest that senescent tumor cells can potentially contribute to cancer relapse by acquiring proliferative properties. The use of senolytic agents after induction of senescence by conventional or targeted therapies allows for the clearance of residual (possibly dormant) senescent tumor cells, which could serve to suppress disease recurrence and cancer mortality.
Citation Format: Tareq Saleh, Liliya Tyutyunyk-Massey, Graeme F. Murray, Moureq R. Alotaibi, Ajinkya S. Kawale, Zeinab Elsayed, Scott C. Henderson, Vasily Yakovlev, Lynne W. Elmore, Amir Toor, Hisashi Harada, Jason Reed, Joseph W. Landry, David A. Gewirtz. Elimination of senescent tumor cells by ABT263 interferes with proliferative recovery and provides a two-hit therapeutic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 901.