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.
journal_name
Cancer Celljournal_title
Cancer cellauthors
Fang Y,McGrail DJ,Sun C,Labrie M,Chen X,Zhang D,Ju Z,Vellano CP,Lu Y,Li Y,Jeong KJ,Ding Z,Liang J,Wang SW,Dai H,Lee S,Sahni N,Mercado-Uribe I,Kim TB,Chen K,Lin SY,Peng G,Westin SN,Liu J,O'Connor MJ,Yap Tdoi
10.1016/j.ccell.2019.05.001subject
Has Abstractpub_date
2019-06-10 00:00:00pages
851-867.e7issue
6eissn
1535-6108issn
1878-3686pii
S1535-6108(19)30224-7journal_volume
35pub_type
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