Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy.

Graphical abstract from Yong, et al (2019).

Copyright © 2019 Elsevier B.V.

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 TA, Mills GB.

Cancer Cell

June 10, 2019

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 inhibitorsinduces 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 inhibitorspersist 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.

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Last updated: June 21, 2019