@article{c9e08cd86a484013959a6667526fc039,
title = "Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy",
abstract = "We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G2 DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity. Strikingly, while sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models. Fang et al. show that sequential inhibition of PARP (PARPi) and WEE1 or ATR has antitumor efficacy similar to concurrent treatment but reduced toxicity due to the persistence of DNA damage on removal of PARPi and differences in basal replication stress between tumor and normal cells, respectively.",
keywords = "PARP inhibitor, WEE1 inhibitor, replication stress, sequential therapy",
author = "Yong Fang and McGrail, {Daniel J.} and Chaoyang Sun and Marilyne Labrie and Xiaohua Chen and Dong Zhang and Zhenlin Ju and Vellano, {Christopher P.} and Yiling Lu and Yongsheng Li and Jeong, {Kang Jin} and Zhiyong Ding and Jiyong Liang and Wang, {Steven W.} and Hui Dai and Sanghoon Lee and Nidhi Sahni and Imelda Mercado-Uribe and Kim, {Tae beom} and Ken Chen and Lin, {Shiaw Yih} and Guang Peng and Westin, {Shannon N.} and Jinsong Liu and O'Connor, {Mark J.} and Yap, {Timothy A.} and Mills, {Gordon B.}",
note = "Funding Information: We thank Phil Jones for compounds and Kathy Roby for ID8. Human bone marrow-derived MSCs were from Texas A&M Health Science Center through NIHP40RR017447. Studies were supported by a kind gift from the Adelson Research Foundation , NIH /NCI grants CA217842 , CA217685 , CA098258 , CA210950 , HG008100 , Komen Foundation SAC110052 , Breast Cancer Research Foundation BCRF-17-108 , Ovarian Cancer Research Foundation , CPRIT RP170640 , and CCSG support grant CA016672 to G.B.M., Susan G. Komen grant PDF17483544 to D.J.M. Grants RR160021 and FG-2018-10723 to N.S. Funding Information: We thank Phil Jones for compounds and Kathy Roby for ID8. Human bone marrow-derived MSCs were from Texas A&M Health Science Center through NIHP40RR017447. Studies were supported by a kind gift from the Adelson Research Foundation, NIH/NCI grants CA217842, CA217685, CA098258, CA210950, HG008100, Komen Foundation SAC110052, Breast Cancer Research Foundation BCRF-17-108, Ovarian Cancer Research Foundation, CPRIT RP170640, and CCSG support grant CA016672 to G.B.M. Susan G. Komen grant PDF17483544 to D.J.M. Grants RR160021 and FG-2018-10723 to N.S. Y.F. conceived and performed the experiments and wrote the manuscript. D.J.McG. C.S. M.L. and K.J.J. performed the experiments. Z.J. and Y.Li analyzed RPPA performed by X.C. C.P.V. and Y.Lu, D.Z. S.W.W. and H.D. conducted immunohistochemical staining. D.Z. I.M.-U. and S.L. performed mouse studies. Y.Li, K.C. and T.-B.K. analyzed T200.2 results. Z.D. S.-Y.L. G.P. M.J.O'C. T.A.Y. S.N.W. N.S. and J.L. provided expertise and feedback. G.B.M. conceived and coordinated the project and wrote the manuscript. G.B.M. consults with AstraZeneca, ImmunoMET, Ionis, Nuevolution, PDX bio, Signalchem, Symphogen, and Tarveda, has stock options with Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, and Tarveda, sponsored research from AstraZeneca, Immunomet, Pfizer, Nanostring, and Tesaro, travel support from Chrysallis Bio, and has licensed technology to Nanostring and Myriad Genetics. T.A.Y. consults with AstraZeneca, Pfizer, EMD Serono, Clovis, BMS, Ignyta, Roche, Janssen, Atrin, Aduro, and Almac, has sponsored research from AstraZeneca and Vertex and travel support from AstraZeneca, BMS, MSD, Vertex, GSK, EMD Serono, and Tesaro. G.P. has sponsored research from Pfizer. S.N.W. consults for AstraZeneca, Clovis Oncology, Medivation, Merck, Ovation, Pfizer, Roche/Genentech, Takeda, Tesaro, and Vermillion. S.N.W. has sponsored research from AstraZeneca, ArQule, Bayer, Clovis Oncology, Cotinga, Novartis, Roche/Genetech, and Tesaro. M.J.O'C. is an AstraZeneca full-time employee and shareholder. Funding Information: G.B.M. consults with AstraZeneca, ImmunoMET, Ionis, Nuevolution, PDX bio, Signalchem, Symphogen, and Tarveda, has stock options with Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, and Tarveda, sponsored research from AstraZeneca , Immunomet , Pfizer , Nanostring , and Tesaro , travel support from Chrysallis Bio, and has licensed technology to Nanostring and Myriad Genetics. T.A.Y. consults with AstraZeneca, Pfizer, EMD Serono, Clovis, BMS, Ignyta, Roche, Janssen, Atrin, Aduro, and Almac, has sponsored research from AstraZeneca and Vertex and travel support from AstraZeneca, BMS, MSD, Vertex, GSK, EMD Serono, and Tesaro. G.P. has sponsored research from Pfizer. S.N.W. consults for AstraZeneca, Clovis Oncology, Medivation, Merck, Ovation, Pfizer, Roche/Genentech, Takeda, Tesaro, and Vermillion. S.N.W. has sponsored research from AstraZeneca, ArQule , Bayer , Clovis Oncology , Cotinga , Novartis , Roche /Genetech, and Tesaro. M.J.O'C. is an AstraZeneca full-time employee and shareholder. Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = jun,
day = "10",
doi = "10.1016/j.ccell.2019.05.001",
language = "English (US)",
volume = "35",
pages = "851--867.e7",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}