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Molecular Targets for Therapy

Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies

Leukemia volume 29, pages 27–37 (2015)Cite this article

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Abstract

Direct targeting of rat sarcoma (RAS), which is frequently mutated, has proven to be challenging, and inhibition of individual downstream RAS mediators has resulted in limited clinical efficacy. We designed a chemical screen to identify compounds capable of potentiating mammalian target of rapamycin (mTOR) inhibition in mutant RAS-positive leukemia, and identified a Wee1 inhibitor. Synergy was observed in both mutant neuroblastoma RAS viral oncogene homolog (NRAS)- and mutant kirsten RAS viral oncogene homolog (KRAS)-positive acute myelogenous leukemia (AML) cell lines and primary patient samples. The observed synergy enhanced dephosphorylation of AKT, 4E-binding protein 1 and s6 kinase, and correlated with increased apoptosis. The specificity of Wee1 as the target of MK-1775 was validated by Wee1 knockdown, as well as partial reversal of drug combination-induced apoptosis by a cyclin-dependent kinase 1 (CDK1) inhibitor. Importantly, we also extended our findings to other mutant RAS-expressing malignancies, including mutant NRAS-positive melanoma, and mutant KRAS-positive colorectal cancer, pancreatic cancer and lung cancer. We observed favorable responses with combined Wee1/mTOR inhibition in human cancer cell lines from multiple malignancies, and inhibition of tumor growth in in vivo models of mutant KRAS lung cancer and leukemia. The present study introduces for the first time Wee1 inhibition combined with mTOR inhibition as a novel therapeutic strategy for the selective treatment of mutant RAS-positive leukemia and other mutant RAS-expressing malignancies.

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Acknowledgements

We wish to acknowledge Catherine Sypher, Carmen Da Silva, Elsy Moreno, Lia Palazzolo and Daisy Moreno for their assistance with in vivo studies. NG is supported by NIH LINCS grant HG006097. MS is supported by NIH grant CA134660.

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Author notes

  1. E Weisberg and A Nonami: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA,

    E Weisberg, A Nonami, Z Chen, M Sattler, E Nelson, K Cowens, A L Christie, C Mitsiades, K-K Wong & J D Griffin

  2. High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, People's Republic of China

    F Liu & Q Liu

  3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    J Zhang & N Gray

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Correspondence to E Weisberg or J D Griffin.

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JDG receives research support and has a financial interest with Novartis Pharma AG. The remaining authors declare no conflict of interest.

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Weisberg, E., Nonami, A., Chen, Z. et al. Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies. Leukemia 29, 27–37 (2015). https://doi.org/10.1038/leu.2014.149

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