Abstract 895: Activating transcription factor 3 (ATF3) down-regulation correlates with platinum resistance in non-small cell lung cancer (NSCLC).
Authors: Jair Bar, Ivan Gorn-Hondermann, Reid Stephanie, Patricia Moretto, Iris Shiran, Shlomit Jessel, Marina Perelman, Eyal Heller, Iris Kamer, Inbal Daniel-Meshulam, Glenwood D. Goss, Jim Dimitroulakos
Journal: Cancer Research (2013)

Abstract Background: NSCLC is the most common cause of cancer-related death. Platinum-based chemotherapy is the mainstay of treatment, but a variety of mechanisms lead to platinum-resistance. ATF3 is a transcription factor, activated in response to a wide variety of stress signals including DNA damage and hypoxia. We recently demonstrated a role for ATF3 as an important regulator of platinum-induced cytotoxicity. In this study, we hypothesize that ATF3 expression correlates with platinum-sensitivity/resistance in NSCLC. Methods: ATF3 induction was examined by Western blots and real-time RT-PCR in isogenic sets of platinum- sensitive (S) or induced resistant (R) NSCLC cell lines. A 1200 compound library was screened to identify platinum-sensitizers in both sets of cell lines. Complete RNA sequencing (RNA-seq) was performed in parental (S) and resistant (R) derived cell lines comparing expression patterns of either untreated or platinum treated cells. Similarly, platinum R and S tumors were identified by screening NSCLC patients’ clinical records and expression patterns compared with RNA-seq analysis. Results: Both mRNA and potein levels of ATF3 were induced 35-120 fold (mRNA) by cisplatin treatment in S cell lines, but only 1-12 fold (mRNA) in the corresponding R lines. The 1200 compound library screen of FDA approved compounds identified several commonly used chemotherapeutic agents as sensitizers of platinum cytotoxicity, as well as vorinostat, a histone deacetylase inhibitor that sensitized only S but not R cell lines. An analogue of this agent, M344, enhanced ATF3 induction and cisplatin cytotoxicity in the S lines but not in the R lines. Comparing RNA-seq results of the S and R lines revealed up-regulation of GADD45A, ATF3 and DDIT3/CHOP in the S but not R cell lines. Comparing samples of S and R NSCLC tumors by RNA-seq demonstrated ATF3 to be among the five genes significantly up-regulated in the S tumors compared to the R tumors. Conclusions: Stress-induced ATF3 is correlated with platinum-sensitivity in NSCLC cells. Tumor ATF3 levels represent a potential predictive marker of response to platinum-based treatment in NSCLC. Revealing the mechanism of ATF3 induction by platinum may lead to the identification of novel platinum-sensitizing therapeutic targets. Citation Format: Jair Bar, Ivan Gorn-Hondermann, Reid Stephanie, Patricia Moretto, Iris Shiran, Shlomit Jessel, Marina Perelman, Eyal Heller, Iris Kamer, Inbal Daniel-Meshulam, Glenwood D. Goss, Jim Dimitroulakos. Activating transcription factor 3 (ATF3) down-regulation correlates with platinum resistance in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 895. doi:10.1158/1538-7445.AM2013-895