Abstract

Drug resistance is a major hurdle in oncology. Responses of acute myeloid leukaemia (AML) patients to cytarabine (Ara-C)-based therapies are often short lived with a median overall survival of months1,2,3,4. Therapies are under development to improve outcomes and include targeting the eukaryotic translation initiation factor (eIF4E) with its inhibitor ribavirin5,6,7. In a Phase II clinical trial in poor prognosis AML5, ribavirin monotherapy yielded promising responses including remissions; however, all patients relapsed. Here we identify a novel form of drug resistance to ribavirin and Ara-C. We observe that the sonic hedgehog transcription factor glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes are elevated in resistant cells. UGT1As add glucuronic acid to many drugs, modifying their activity in diverse tissues8. GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and Ara-C, and thus drug resistance. Resistance is overcome by genetic or pharmacological inhibition of GLI1, revealing a potential strategy to overcome drug resistance in some patients.

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Acknowledgements

We are grateful for reading of the manuscript by A. Kentsis, M. Osborne, F. Pettersson, S. del Rincon and C. Perreault. We are grateful for the use of Pharmascience facilities thanks to M. Goodman and D. Goodman, for specimens from the Banques de Cellules Leucémiques Du Québec (BCLQ), and for technical discussions with M. Ouellet. We thank nursing and support staff at all the clinical sites, and A. Ramteke for technical support. K.L.B.B. is supported by funds from the National Institutes of Health (RO1 80728 and 98571), IRICoR and Translational Research Program grants from the Leukemia and Lymphoma Society USA. K.L.B.B. holds a Canada Research Chair and H.A.Z. holds a Cole Foundation Fellowship and a CNRS Lebanon Fellowship.

Author information

Author notes

    • James B. Jaquith

    Present address: JAQJAM Consulting, Montreal J7V 9B6, Canada.

Affiliations

  1. Institute for Research in Immunology and Cancer and Department of Pathology and Cell Biology, Université de Montréal, P.O. Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada

    • Hiba Ahmad Zahreddine
    • , Biljana Culjkovic-Kraljacic
    • , Patrick Gendron
    • , Gregory Cormack
    • , Abdellatif Amri
    •  & Katherine L. B. Borden
  2. Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montréal, Québec H3T 1E2, Canada

    • Sarit Assouline
    • , Eftihia Cocolakis
    •  & Wilson H. Miller
  3. Pharmascience Inc., 6111 Royalmount Avenue, Montreal, Quebec H4P 2T4, Canada

    • Andrea A. Romeo
    • , Stephen J. Morris
    •  & James B. Jaquith
  4. Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 1305 York Avenue, New York, New York 10021, USA

    • Leandro Cerchietti
  5. Hôpital Maisonneuve-Rosemont, 5415 Boulevard de l’Assomption, Montréal, Québec H1T 2M4, Canada

    • Julie Bergeron
  6. McMaster University/Hamilton Health Sciences, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada

    • Brian Leber
  7. Department of Medicine, Division of Hematology/Oncology, 601 Elmwood Avenue, University of Rochester, Rochester, New York 14627, USA

    • Michael W. Becker
  8. Division of Hematology, Department of Medicine, University of Colorado Denver, 13123 East 16th Avenue, Aurora, Colorado 80045, USA

    • Shanshan Pei
    •  & Craig T. Jordan

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Contributions

H.A.Z. and B.C.-K. designed and performed experiments, analysed data and wrote the manuscript; L.C., A.A. and G.C. performed experiments; P.G., S.P. and C.T.J. analysed data; A.A.R. performed experiments and analysed data; J.B.J. and S.J.M. designed experiments; S.A. was medical monitor for the trial, treated patients and analysed clinical data; E.C. coordinated clinical trials and analysed clinical data; B.L., J.B. and M.W.B. treated patients, provided specimens and analysed clinical data; W.H.M. designed experiments, analysed data and edited the manuscript; K.L.B.B. designed experiments, analysed data and wrote the manuscript.

Competing interests

S.J.M., J.B.J. and A.A.R. are/were employees of Pharmascience.

Corresponding author

Correspondence to Katherine L. B. Borden.

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DOI

https://doi.org/10.1038/nature13283

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