Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis
Amirali B. Bukhari, … , Gordon K. Chan, Armin M. Gamper
Amirali B. Bukhari, … , Gordon K. Chan, Armin M. Gamper
Published January 15, 2019
Citation Information: J Clin Invest. 2019;129(3):1329-1344. https://doi.org/10.1172/JCI122622.
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Research Article Oncology

Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis

Abstract

We used the cancer-intrinsic property of oncogene-induced DNA damage as the base for a conditional synthetic lethality approach. To target mechanisms important for cancer cell adaptation to genotoxic stress and thereby to achieve cancer cell–specific killing, we combined inhibition of the kinases ATR and Wee1. Wee1 regulates cell cycle progression, whereas ATR is an apical kinase in the DNA-damage response. In an orthotopic breast cancer model, tumor-selective synthetic lethality of the combination of bioavailable ATR and Wee1 inhibitors led to tumor remission and inhibited metastasis with minimal side effects. ATR and Wee1 inhibition had a higher synergistic effect in cancer stem cells than in bulk cancer cells, compensating for the lower sensitivity of cancer stem cells to the individual drugs. Mechanistically, the combination treatment caused cells with unrepaired or under-replicated DNA to enter mitosis leading to mitotic catastrophe. As these inhibitors of ATR and Wee1 are already in phase I/II clinical trials, this knowledge could soon be translated into the clinic, especially as we showed that the combination treatment targets a wide range of tumor cells. Particularly, the antimetastatic effect of combined Wee1/ATR inhibition and the low toxicity of ATR inhibitors compared with Chk1 inhibitors have great clinical potential.

Authors

Amirali B. Bukhari, Cody W. Lewis, Joanna J. Pearce, Deandra Luong, Gordon K. Chan, Armin M. Gamper

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Figure 8

Synergistic killing of breast cancer stem cells by ATR and Wee1 inhibitors.

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Synergistic killing of breast cancer stem cells by ATR and Wee1 inhibito...
(A) Isolation of cancer stem cell–enriched subpopulations (side population, SP) from MDA-MB-231 or MCF7 based on their increased dye (DyeCycle Violet, DCV; see supplemental methods) efflux properties. Verapamil, an inhibitor of drug efflux pump proteins, particularly of the ABC transporter family, served as negative control. (B) Isolated SPs show an increased ability to form mammospheres compared with control subpopulations (non–side population, NSP). Representative images of mammospheres are shown. (C and D) Four-day survival assays of cancer stem cell–enriched SPs and control cells (NSPs) isolated from MDA-MB-231 (C) and MCF7 (D). Plated cells were treated with indicated concentrations of AZD1775 and/or AZD6738. Color bars indicate percentage survival normalized to untreated cells. (E) Model of cancer-selective synergistic cell killing by combined ATR and Wee1 inhibition. Cancer cells have higher baseline levels of genotoxic stress than normal cells. Wee1 inhibition increases genotoxic stress, while ATR and Wee1 inhibition together lower cellular DNA-damage response capacity (in the simplified model to the same extent, but potentially higher in cancer cells relying on these 2 kinases for survival). A therapeutic window is created for the selective killing of cancer cells. (F) Cell cycle–dependent effects of ATR and Wee1 inhibition contributing to overall cell death following mitotic catastrophe. HR, homologous recombination.