@article{9e8a7e4bc89641558a99b501c5f1f9ce,
title = "The non-canonical target PARP16 contributes to polypharmacology of the PARP inhibitor talazoparib and its synergy with WEE1 inhibitors",
abstract = "PARP inhibitors (PARPis) display single-agent anticancer activity in small cell lung cancer (SCLC) and other neuroendocrine tumors independent of BRCA1/2 mutations. Here, we determine the differential efficacy of multiple clinical PARPis in SCLC cells. Compared with the other PARPis rucaparib, olaparib, and niraparib, talazoparib displays the highest potency across SCLC, including SLFN11-negative cells. Chemical proteomics identifies PARP16 as a unique talazoparib target in addition to PARP1. Silencing PARP16 significantly reduces cell survival, particularly in combination with PARP1 inhibition. Drug combination screening reveals talazoparib synergy with the WEE1/PLK1 inhibitor adavosertib. Global phosphoproteomics identifies disparate effects on cell-cycle and DNA damage signaling thereby illustrating underlying mechanisms of synergy, which is more pronounced for talazoparib than olaparib. Notably, silencing PARP16 further reduces cell survival in combination with olaparib and adavosertib. Together, these data suggest that PARP16 contributes to talazoparib's overall mechanism of action and constitutes an actionable target in SCLC.",
keywords = "Ewing's sarcoma, PARP inhibitor, PARP1, PARP16, adavosertib, lung cancer, off-target, polypharmacology, proteomics, talazoparib",
author = "Vinayak Palve and Knezevic, {Claire E.} and Bejan, {Daniel S.} and Yunting Luo and Xueli Li and Silvia Novakova and Welsh, {Eric A.} and Bin Fang and Fumi Kinose and Haura, {Eric B.} and Monteiro, {Alvaro N.} and Koomen, {John M.} and Cohen, {Michael S.} and Lawrence, {Harshani R.} and Uwe Rix",
note = "Funding Information: This work was supported by the NIH/NCI R01 CA181746 (to U.R.), the NIH/NCI R50 CA211447 (to H.R.L.), the V Foundation, Miles for Moffitt and the H. Lee Moffitt Cancer Center and Research Institute. We further wish to acknowledge the Moffitt Lung Cancer Center of Excellence and the Moffitt Chemical Biology (Chemistry Unit), Proteomics & Metabolomics, and Cancer Informatics Core Facilities. Moffitt Core Facilities are supported by the National Cancer Institute (award no. P30-CA076292) as a Cancer Center Support Grant. The Proteomics and Metabolomics Core is also supported by the Moffitt Foundation. Conceptualization, V.P. C.E.K. and U.R.; investigation, V.P. C.E.K. D.S.B. Y.L. X.L. S.N. E.A.W. B.F. F.K. and U.R.; formal analysis, V.P. E.A.W. and U.R.; writing – original draft, V.P. and U.R.; writing – review & editing, all authors; funding acquisition, H.R.L. and U.R.; visualization, V.P. and U.R.; supervision, J.M.K. M.S.C. H.R.L. and U.R. The authors declare no competing interests. Funding Information: This work was supported by the NIH / NCI R01 CA181746 (to U.R.), the NIH / NCI R50 CA211447 (to H.R.L.), the V Foundation , Miles for Moffitt and the H. Lee Moffitt Cancer Center and Research Institute . We further wish to acknowledge the Moffitt Lung Cancer Center of Excellence and the Moffitt Chemical Biology (Chemistry Unit), Proteomics & Metabolomics, and Cancer Informatics Core Facilities. Moffitt Core Facilities are supported by the National Cancer Institute (award no. P30-CA076292 ) as a Cancer Center Support Grant. The Proteomics and Metabolomics Core is also supported by the Moffitt Foundation . Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",
year = "2022",
month = feb,
day = "17",
doi = "10.1016/j.chembiol.2021.07.008",
language = "English (US)",
volume = "29",
pages = "202--214.e7",
journal = "Cell Chemical Biology",
issn = "2451-9456",
publisher = "Elsevier Inc.",
number = "2",
}