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: | Tarafdar, Ms Anuradha and Moka, Miss Hothri Ananyamb and Morrison, Miss Heather and Kinstrie, Dr Ross and Holyoake, Professor Tessa and Irvine, Dr David and Nixon, Mr Colin and Campbell, Dr Victoria and Copland, Professor Mhairi and Wheadon, Professor Helen |
| 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 > School 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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