Abstract 2822: ATR inhibitors are active as single agents and in combination with PARP1 and ATM inhibitors in molecularly distinct subsets of small cell lung cancer models
Authors: Gay Carl M. , Tong Pan , Li Lerong , Stewart C. Allison , Sen Triparna , Glisson Bonnie S. , Heymach John V. , Wang Jing , Byers Lauren Averett 
Published: August 2018

Abstract
Small cell lung cancer (SCLC) is an aggressive form of lung cancer, notable for rapid emergence of drug resistance following initial chemotherapy. Rates of five-year overall survival are only 7% across all stages and only one drug, topotecan, is approved by the FDA for recurrent SCLC. As a result, the National Cancer Institute has named identifying novel vulnerabilities in SCLC as an urgent area of need. Increased expression, relative to non-small cell lung cancer (NSCLC), of numerous components of the DNA damage response (DDR) pathway, including poly (ADP-Ribose) polymerase 1 (PARP1) and ataxia telangiectasia mutated (ATM), is observed in SCLC. Thus, targeting DDR has emerged as an attractive therapeutic strategy in SCLC, bolstered by recent data demonstrating activity of PARP1 inhibitors (PARPi) in SCLC patients. Interestingly, data suggest that PARPi resistant models from other tumors may rely on another DDR component, ataxia telangiectasia and Rad3 related protein (ATR), for survival. ATR/ATR is also highly expressed in SCLC compared to NSCLC and normal lung tissue. Preclinical data have shown that treatment with ATR inhibitors (ATRi) is especially effective in p53- and ATM-deficient tumor models, a notable fact given that SCLC is universally p53-mutant and that ATM-mutant and ATM-deficient SCLC is a small, but significant proportion of all SCLC. We treated 22 human-derived SCLC cell line models with two clinically relevant ATRi, VX-970 (formerly VE-822) and AZD-6738, and observed single agent activity of both ATR inhibitors in a significant number of cell lines, with half-maximal inhibitory concentrations (IC50s) as low as 30 nM and &gt;100-fold difference in IC50s between the most and least sensitive cell lines. Utilizing extensive genomic, transcriptomic and proteomic characterization of these cell lines, we then identified predictive biomarkers of response to ATRi in SCLC, including low ATM expression. As low ATM was associated with ATRi sensitivity, we tested whether the addition of an ATM inhibitor (AZD-0156) may further sensitize SCLC models to ATRi. We treated 12 SCLC cell lines with AZD-6738 and AZD-0156 in combination and identified a subset of lines in which synergy is observed between the two agents. Similarly, as targeting ATR has been shown to overcome PARPi resistance in other cancer types, we treated 12 SCLC cell lines with the ATRi AZD-6738 and the PARPi olaparib in combination and again observed a subset of lines in which the two agents acted synergistically. Interestingly, the lines in which ATRi+ATMi and ATRi+PARPi synergy is observed are distinct and include lines that were the most resistant to single-agent AZD-6738. Together, these data support further investigation of ATRi in SCLC and suggest that via the use of ATRi alone or in combination with ATMi or PARPi, multiple molecularly distinct subsets of SCLC can be effectively targeted.
Citation Format: Carl M. Gay, Pan Tong, Lerong Li, C. Allison Stewart, Triparna Sen, Bonnie S. Glisson, John V. Heymach, Jing Wang, Lauren Averett Byers. ATR inhibitors are active as single agents and in combination with PARP1 and ATM inhibitors in molecularly distinct subsets of small cell lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2822.