Abstract 1033: Alternative tumor suppressor mechanisms in lung carcinomas - modulation of senescence by growth factor-induced signaling

Abstract

Abstract Cellular signaling pathways integrate multiple intra- and extracellular signals and thereby influence cell fate. Outcome of oncogene-targeted pharmacotherapies (cell cycle inhibition, apoptosis, senescence, autophagy) depends on variable factors (e.g. compound, dose, duration, cellular genetic background etc.). Oncogene-induced senescence is recognized as an important tumor-suppressive mechanism, bypassing of which may contribute to malignant transformation of the cells. On the other hand, senescence induction, in addition to apoptosis stimulation and proliferation suppression, is responsible for the cytostatic activity of many commonly used anticancer drugs. Therefore, senescence escape must be considered as an important drug-resistance factor. In our work we characterize,,DNA Damage-independent” senescence induced by tyrosine kinase inhibitors (TKI) and growth factor deprivation of non-small cell lung cancer (NSCLC) cell lines and other EGFR-dependent cells. Treatment of different cell lines with various concentrations of EGFR-TKIs was followed by the assessment of cell fate (i.e. apoptosis, cell cycle distribution, senescence and clonogenic survival) as well as intracellular signaling. We could show that treatment of EGFR-dependent cells with specific EGF receptor tyrosine kinase inhibitors (EGFR-TKI) can lead to generation of reactive oxygen species (ROS), activation of a DNA damage response (DDR) program and cellular senescence. Surprisingly, under certain experimental conditions DDR activation was found to be independent from detectable DNA damage. Key players of DDR signaling were shown to be essential for senescence induction. Molecular dissection of crucial signaling nodes and molecular switches involved in modulation of cell fate in oncogene dependent cells treated with specific EGFR-inhibitors is currently being performed. Furthermore, our work is focussed on the identification and characterization of cellular factors activating DNA damage response (DDR) pathways in the absence of DNA damage under certain experimental conditions. Understanding the interplay between theses decision making pathways either leading to proliferative arrest, cellular senescence or apoptosis will help improve current pharmacotherapies and develop new therapeutic approaches. Note: This abstract was not presented at the meeting. Citation Format: Boyka Markova, Frank Breitenbuecher, Martin Schuler. Alternative tumor suppressor mechanisms in lung carcinomas - modulation of senescence by growth factor-induced signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1033. doi:10.1158/1538-7445.AM2015-1033