Background: Small cell lung cancer (SCLC) is a highly aggressive type of neuroendocrine tumor with a low survival rate, signifying an unmet medical need. Although PARP inhibitors (PARPis) display single-agent anticancer activity in SCLC, the underlying biology is poorly understood. In the present study, we determined the differential efficacy of multiple clinically relevant PARPis and identified a novel non-canonical and actionable PARPi target in SCLC. Methods: A panel of SCLC cell lines was analyzed for sensitivity to PARPis using the Cell Titer Glow (CTG) viability assay. Chemical proteomics and western blotting were performed to investigate the targets of PARPis. The effect of PARP16 on cell viability was analyzed using RNA interference. Drug combination screening for inhibition of viability was performed, network-wide signaling changes were determined using phosphoproteomics, and efficacy of drug combinations was determined in ex vivo PDX clonogenic assays. Results: Compared to other clinically relevant PARPis (rucaparib, olaparib, niraparib) talazoparib displayed the highest potency across a panel of SCLC cell lines, including cells negative for SLFN11, which has been suggested to indicate PARPi sensitivity. Subsequent chemical proteomics with SLFN11-negative SCLC cells identified the non-canonical PARP family member PARP16 as a unique talazoparib target, along with the eminent PARP1. Transient knockdown of PARP16 significantly reduced cell survival in certain SCLC cell lines, particularly in combination with olaparib. Furthermore, drug combination screens revealed synergistic activity of talazoparib when combined with the WEE1 inhibitor adavosertib in SCLC cells, which was more pronounced than the combination of adavosertib with olaparib, which has no activity against PARP16. Silencing of PARP16, in combination with olaparib and adavosertib, with enhanced cell killing, and global phosphoproteomics identified network-wide signaling crosstalk inhibition by the talazoparib/adavosertib drug combination. Conclusion: Our data suggest that in addition to the well-studied PARP1 targeting mechanism, PARP16, a non-canonical member of the PARP family, is likely involved in talazoparib’s overall mechanism of action and may constitute a novel actionable target in SCLC.

Citation Format: Vinayak Palve, Clare Knezevic, Yunting Luo, Xueli Li, Slivia Novakova, Eric Welsh, Bin Fang, Fumi Kinose, Eric B Haura, Alvaro N Monteiro, John M Koomen, Harshani R Lawrence, Uwe Rix. PARP16 is a novel target of talazoparib which contributes to synergy with adavosertib in SCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B021. doi:10.1158/1535-7163.TARG-19-B021