Cancer Cell
Volume 35, Issue 6, 10 June 2019, Pages 851-867.e7
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Article
Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy

https://doi.org/10.1016/j.ccell.2019.05.001Get rights and content
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Highlights

  • We characterize effects of PARP and WEE1 inhibitors on functional proteomics

  • Concurrent PARP and WEE1 blockade effectively inhibits tumors but is poorly tolerated

  • Sequential PARP and WEE1 inhibition minimizes toxicity while maintaining efficacy

  • Basal replication stress influences the therapeutic index of sequential therapy

Summary

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.

Keywords

PARP inhibitor
WEE1 inhibitor
sequential therapy
replication stress

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