| Literature DB >> 31185210 |
Yong Fang1, Daniel J McGrail2, Chaoyang Sun3, Marilyne Labrie4, Xiaohua Chen2, Dong Zhang4, Zhenlin Ju2, Christopher P Vellano2, Yiling Lu2, Yongsheng Li2, Kang Jin Jeong4, Zhiyong Ding2, Jiyong Liang2, Steven W Wang2, Hui Dai2, Sanghoon Lee2, Nidhi Sahni5, Imelda Mercado-Uribe6, Tae-Beom Kim7, Ken Chen7, Shiaw-Yih Lin2, Guang Peng8, Shannon N Westin9, Jinsong Liu6, Mark J O'Connor10, Timothy A Yap11, Gordon B Mills4.
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. Published by Elsevier Inc.Entities:
Keywords: PARP inhibitor; WEE1 inhibitor; replication stress; sequential therapy
Mesh：
Substances：
Year: 2019 PMID： 31185210 PMCID： PMC6642675 DOI： 10.1016/j.ccell.2019.05.001
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743