Article | Published:

Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia

Nature volume 513, pages 512516 (25 September 2014) | Download Citation

Abstract

Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and KrasG12D mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to γ-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Expression profiling data have been deposited in the Gene Expression Omnibus under accession number GSE48260.

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Acknowledgements

This work was supported by grants from the William Lawrence and Blanche Hughes Foundation to J.C.A. and K.S.; by Specialized Center of Research (SCOR) awards 7019 and 7703 from the Leukaemia and Lymphoma Society of America; by National Institutes of Health grants R37 CA72614 and R01 CA180037 (to K.S.), K99 CA157950 (to M.D.), K08 CA134649 (to Q.L.) and P01 CA119070 (to J.C.A. and W.S.P.), and by the ALSAC of St. Jude Children’s Research Hospital (J.R.D.). K.A. is supported by the Ohio Supercomputer Center (#PAS0425) and is an Ohio Cancer Research Associate (#GRT00024299); and J.X received a Research Fellowship from the American Cancer Society (ACS). K.S. is an ACS Research Professor. We are grateful to T. Jacks and D. Tuveson for KrasG12D mice; to L. Wolff for the MOL4070 virus; and to D. Largaespada and G. Narla for sharing their advice and expertise.

Author information

Affiliations

  1. Department of Pediatrics and Benniof Children’s Hospital, University of California, San Francisco, California 94143, USA

    • Monique Dail
    • , Jason Wong
    • , Jessica Lawrence
    • , Daniel O’Connor
    • , Jin Xu
    •  & Kevin Shannon
  2. Department of Pathology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Joy Nakitandwe
    • , Shann-Ching Chen
    •  & James R. Downing
  3. Department of Translational Oncology, Genentech Inc., South San Francisco, California 94080, USA

    • Leslie B. Lee
    •  & Deepak Sampath
  4. Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio 43210, USA

    • Keiko Akagi
  5. Division of Haematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Qing Li
  6. Department of Pathology, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Jon C. Aster
  7. Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Warren S. Pear

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Contributions

M.D., J.R.D., D.S. and K.S. designed experiments and analysed the data. M.D., J.W., J.L., D.O’C., J.N. and L.B.L. performed experiments. S.-C.C. and K.A. provided bioinformatics analysis. J.X., J.C.A., W.S.P., Q.L. and D.S. provided reagents. J.C.A., W.S.P., J.R.D. and D.S. provided conceptual advice. M.D. and K.S. wrote the manuscript.

Competing interests

D.S. and L.B.L. are fulltime employees of Genentech Inc.

Corresponding author

Correspondence to Kevin Shannon.

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DOI

https://doi.org/10.1038/nature13495

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