Abstract 5470: Reversibility of therapy-induced senescence in non-small cell lung cancer as a model of cancer recurrence

Abstract

Abstract Disease recurrence at either primary or metastatic tumor sites arising from dormant tumors is largely responsible for the morbidity and mortality of many cancers. Although cellular quiescence has been proposed as a mechanism of dormancy, the nature of the growth arrest that allows tumor cells to re-emerge months or years after treatment has never been directly determined. The current work was designed to examine the hypothesis that the senescence induced by cancer chemotherapeutic drugs could be reversible, with implications for tumor dormancy and disease recurrence. Studies were performed using etoposide in models of non-small cell lung cancer (NSCLC). Exposure to etoposide at sublethal concentrations resulted in growth arrest accompanied by the induction of senescence and autophagy. Growth arrest was transient in that proliferative recovery was evident by day 7 post-etoposide exposure. Analysis of senescence based on β-galactosidase activity demonstrated that the restoration of proliferative capacity coincided with a decline in the extent of senescence. Real-time live microscopy demonstrated heterogeneous fates of senescent cells, where the bulk of the cell population remaining in a state of stasis, a subset of cells undergoing apoptosis, and a fraction of the large, flattened, and polyploid cells spontaneously entering into mitosis. Neither genetic nor pharmacological inhibition of autophagy influenced the senescence response to etoposide, the eventual proliferative recovery, or sensitivity to etoposide. These findings indicate that the induction and resolution of senescence is independent of the accompanying autophagy, and that the autophagy induced by etoposide is non-cytoprotective in function. These observations suggest that therapy-induced senescence may ultimately be a transient process in that at least a subpopulation of tumor cells can and will regain proliferative capacity. Consequently, therapy-induced senescence could potentially be studied as a model of tumor dormancy, and the reversibility of senescence as a model of disease recurrence. Citation Format: Tareq Saleh, Emmanuel K. Cudjoe, S Lauren Kyte, Scott C. Henderson, Lynne W. Elmore, David A. Gewirtz. Reversibility of therapy-induced senescence in non-small cell lung cancer as a model of cancer recurrence [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 5470. doi:10.1158/1538-7445.AM2017-5470