title: Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia.
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.
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0XB, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Irvine
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Centre, Duarte, CA, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0XB, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Kinstrie
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0XB, UK.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Tarafdar
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0XB, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Morrison
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0XB, UK.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Campbell
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0XB, UK.
authors.forename: Hothri A
authors.initials: HA
authors.lastname: Moka
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Centre, Duarte, CA, USA.
authors.forename: Yinwei
authors.initials: Y
authors.lastname: Ho
authors.affiliation: Histology, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Rd, Glasgow G61 1BD, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0XB, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Wheadon
authors.affiliation: Department of Histology, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Goodlad
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0XB, UK.
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.affiliation: Division of Hematology-Oncology, University of Alabama Birmingham, Birmingham, AL, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0XB, UK.
authors.forename: Mhairi
authors.initials: M
authors.lastname: Copland
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology; D013154:Spleen / Q000473:pathology
chemical_list: D018952:Antigens, CD34; D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D011725:Pyridines; D011743:Pyrimidines; D054852:Small Molecule Libraries; C561435:sonidegib; C498826:nilotinib