Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia

Irvine, D. A. et al. (2016) Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia. Scientific Reports, 6, 25476. (doi: 10.1038/srep25476) (PMID:27157927) (PMCID:PMC4860619)

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Abstract

Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34+ CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34+ CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34+ CP-CML cell engraftment in NSG mice and, upon administration to EGFP+ /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kinstrie, Dr Ross and Holyoake, Professor Tessa and Nixon, Mr Colin and Campbell, Dr Victoria and Copland, Professor Mhairi and Wheadon, Dr Helen and Tarafdar, Ms Anuradha and Moka, Miss Hothri Ananyamb and Morrison, Miss Heather and Irvine, Dr David
Authors: Irvine, D. A., Zhang, B., Kinstrie, R., Tarafdar, A., Morrison, H., Campbell, V. L., Moka, H. A., Ho, Y., Nixon, C., Manley, P. W., Wheadon, H., Goodlad, J. R., Holyoake, T. L., Bhatia, R., and Copland, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Scientific Reports 6: 25476
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
506531An investigation of the control of cell division and quiescence in leukaemic versus normal haemopoietic stem and progenitor cellsMhairi CoplandScottish Executive Health Department (SEHHD-CSO)SCD/04RI CANCER SCIENCES
493771Self-renewal pathway manipulation as a potential therapeutic strategy for the eradication of Chronic Myeloid Leukaemia (CML) Stem CellsDavid IrvineScottish Executive Health Department (SEHHD-CSO)CAF/08/09RI CANCER SCIENCES
614931Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative studentshipMhairi CoplandWellcome Trust (WELLCOME)099710/Z/12/ZICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C