Abstract 7: PARP and Bcl-2 co-inhibition in small cell lung cancer (SCLC)

Abstract

Abstract Background: Small cell lung cancer (SCLC) accounts for 10-15% of all lung cancers. SCLC is initially responsive to chemotherapy, but quickly relapses. With few other treatment options available, the 5-year survival rate remains less than 5%. Bcl-2 is an anti-apoptotic protein that is overexpressed in SCLC and is associated with chemotherapy resistance. Previous studies have shown Bcl-2 inhibition to be effective in SCLC cell lines; however, Bcl-2 antagonists, such as GX15-070 (obatoclax mesylate), have been disappointing in clinical trials. We have recently shown that PARP-1, a DNA binding protein involved in single and double strand break repairs, is overexpressed in SCLC and that SCLC models are sensitive to PARP inhibition. As recent work illustrated a synergistic interaction between Bcl-2 antagonists and PARP inhibitors in pancreatic cancer cell lines, we hypothesize that a similar effect may occur in SCLC. Methods: Thirteen SCLC cell lines were treated with GX15-070 ± the PARP inhibitor AZD2281 (olaparib), and proliferation was assayed by CellTiter-Glo. In an effort to identify potential biomarkers of response to combination therapy, drug sensitivities (IC50 values) were correlated with proteomic profiling data generated by reverse phase protein array (RPPA), which measured the expression of 193 total and/or phospho-proteins. Results: As expected, SCLC cell lines exhibited a range of sensitivities to single agent GX15-070 in vitro (0.02-0.40 μM). When AZD2281 (PARP inhibitor) was added to a low dose of GX15-070 (0.03 μM), an additive effect was observed in 6 of 10 cell lines tested. Baseline proteomic profiling by RPPA revealed a number of proteins that correlated with sensitivity to Bcl-2 inhibition, including a pathway connecting high insulin receptor substrate-1 (IRS) to high Bcl-xL, (IRS-1, SGK, FOXO3, BIM, and Bcl-xL). Bcl-xL is also a target of GX15-070. Conclusion: Some SCLC cell lines were sensitive to Bcl-2 inhibition. In contrast to pancreatic cancer, a synergistic interaction was not observed when GX15-070 was combined with AZD2281. This combination showed at best an additive interaction in 6 of 10 SCLC cell lines tested, indicating limited value to the SCLC patient population as a whole. Interestingly, high IRS-1 and Bcl-xL expression may serve as biomarkers of response to GX15-070, suggesting a subset of SCLC patients that may be more sensitive to Bcl-2 inhibition. Our baseline proteomic analysis also suggests novel Bcl-2 inhibitor combinations. Metformin, for example, elevates expression of IRS-1, and its use could further sensitize SCLC to Bcl-2 inhibition. We are currently testing this novel combination in pre-clinical models of SCLC Citation Format: Janaya Shelly, Robert J. Cardnell, Fatemeh Masrorpour, Lixia Diao, Jing Wang, Lauren Byers. PARP and Bcl-2 co-inhibition in small cell lung cancer (SCLC). [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 7. doi:10.1158/1538-7445.AM2015-7