Abstract 3282: Poly (ADP) ribose polymerase (PARP) enzyme inhibitor, CEP8983, potentiates bendamustine activity in small cell lung cancer (SCLC).

Abstract

Abstract Background: Effective therapy for small cell lung cancer (SCLC) is currently limited; therefore new approaches are warranted. High level of expression of PARP enzyme in SCLC suggests a role for this enzyme in the development of resistance to DNA-damaging agents used for treatment of SCLC. We investigated activity of a PARP inhibitor, CEP8983, in combination with bendamustine in SCLC. Methods: In vitro cytotoxicity of bendamustine alone and in combination with CEP8983 was assessed in SCLC cell lines (DMS114, DMS153, DMS53, H526, H146, H69, H187, H209, and H128). Exponentially growing cells were treated by continuous exposure for 72 h to vehicle, CEP8983, Bendamustine or the combination. Surviving cell fraction and growth inhibition was determined using MTS assay. Western blot assay was performed to assess for PARP inhibition; changes in markers of apoptosis (cleaved PARP and caspase), DNA damage (gamma-H2AX) under different treatment conditions. Degree of cisplatin sensitivity previously determined for these cell lines were correlated with bendamustine activity and modulation by CEP8983. Results: CEP8983 showed negligible cytotoxicity as a single agent at relevant concentrations. Bendamustine was cytotoxic to SCLC cell lines with clinically achievable micromolar IC50 concentrations (DMS114 - 73.1μM, DMS153 - 66.4μM, DMS53 - 53.7μM, H526 - 16.0μM, H146 - 34.4μM, H69 - 30.9μM, H187 - 16.1μM, H209 - 51.6μM, and H128 - 6.2μM). The combination of bendamustine and CEP8983 produced a 20 to 80% reduction in IC50 concentrations of bendamustine in 8 of 9 cell lines tested. There was no significant correlation between platinum and bendamustine sensitivity in these cell lines (r=0.199, 95%CI: -0.5364, 0.7623; p=0.6085). There was a strong positive correlation between higher platinum sensitivity of cell lines (indicated by low IC50 concentration of cisplatin) and enhanced cytotoxicity of bendamustine by CEP8983 (r= -0.856, 95%CI: -0.9691,-0.4436; p=0.0033). The combination induced increased gamma-H2AX expression in some of the cell lines suggesting increased apoptosis in the presence of CEP8983. In vivo confirmation of this interaction is pending in xenograft model to be presented at the meeting. Conclusions: Bendamustine cytotoxicity against SCLC cell lines was potentiated by CEP8983, especially in cell lines that were more sensitive to cisplatin. The data support clinical evaluation of this novel combination in patients with SCLC. Citation Format: Taofeek Kunle Owonikoko, Guojing Zhang, Ping Yue, Suresh Ramalingam, Fadlo R. Khuri, Shi-Yong Sun. Poly (ADP) ribose polymerase (PARP) enzyme inhibitor, CEP8983, potentiates bendamustine activity in small cell lung cancer (SCLC). [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 3282. doi:10.1158/1538-7445.AM2013-3282