Abstract 2489: Proteomic profiling identifies PI3K and DNA repair pathways as potential markers of response to PARP inhibitor BMN673 in SCLC.
Authors: Cardnell Robert J. , Feng Ying , Diao Lixia , Fan You Hong , Wang Jing , Shin Yuqiao , Minna John D. , Heymach John V. , Byers Lauren A. 
Published: August 2014

Background: Small cell lung cancer (SCLC) is an aggressive malignancy that accounts for 13% of lung cancers in the US and has a 5-year survival rate &lt;10%. Novel therapeutic approaches are critically needed to improve clinical outcomes. Using proteomic profiling, we previously identified high levels of PARP1 expression in SCLC cell lines and tumors. We also demonstrated in vitro sensitivity of SCLC to two PARP inhibitors, olaparib and rucaparib. Here we explore markers of response and pathways modulated following PARP1 inhibition as a basis for developing potential predictive markers and rational drug combinations.

Methods: Sensitivity of SCLC lines to BMN673 and cisplatin was determined by CellTiter-Glo cell viability assay. Total and phospho-protein expression of 200 markers was measured at baseline and following drug treatment in SCLC cell lines by reverse phase protein array (RPPA). Correlations between baseline protein expression and drug sensitivity were determined by Spearman rank correlation. Modulation of protein expression post treatment was assessed by ANOVA.

Results: The novel PARP inhibitor BMN673 had potent in vitro activity in a panel of 12 SCLC cell lines with IC50’s ranging from 1.7-15nM. A higher expression level of several DNA repair proteins was associated with greater BMN673 sensitivity. For example, protein expression levels of ERCC1, DNA PKcs, ATM, FANCD2, and pChk2 were inversely correlated with IC50 values (Rho values -0.93 to -0.81; p≤0.02). In contrast, high baseline expression of phosphorylated Akt (T308) (R=0.91, p=0.005) and pAkt (S473) (R=0.81, p=0.02) were associated with decreased sensitivity to BMN673. We also observed increased phosphorylation of mTOR, Akt, and S6 (p&lt;0.02) at 24h following PARP inhibitor treatment, suggesting that PI3K/Akt/mTOR pathway activation may be associated with both inherent and acquired resistance. Consistent with clinical studies suggesting greater PARP inhibitor activity in platinum-sensitive tumors, markers of BMN673 response overlapped with markers of cisplatin sensitivity, with higher DNA repair protein levels and lower pAkt levels associated with greater cisplatin activity in vitro in the same SCLC cell line panel.

Conclusions: Here we demonstrate significant, single-agent in vitro activity of the PARP inhibitor BMN673 in SCLC and potential predictive markers of response. Interestingly, for the first time we show an inverse correlation between PARP inhibitor sensitivity and PI3K/Akt/mTOR pathway activation. This observation parallels recent data suggesting that PI3K inhibition may sensitize breast cancer to PARP inhibition and suggests a potential coordinated regulation between DNA repair and PI3K pathways. The activity of BMN673 and these candidate response biomarkers will be further investigated in a Phase I cohort expansion of BMN673 in patients with SCLC.

Citation Format: Robert J. Cardnell, Ying Feng, Lixia Diao, You Hong Fan, Jing Wang, Yuqiao Shin, John D. Minna, John V. Heymach, Lauren A. Byers. Proteomic profiling identifies PI3K and DNA repair pathways as potential markers of response to PARP inhibitor BMN673 in 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 2489. doi:10.1158/1538-7445.AM2013-2489