title: Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML.
abstract: The introduction of imatinib in the treatment of chronic myeloid leukemia (CML) represents the most successful example of targeted therapy in human cancer. However, leukemic stem cells are insensitive to tyrosine kinase inhibitors (TKIs) and contribute to the persistence of disease by representing a reservoir of selfrenewing cells that replenish the disease after drug discontinuation. This finding has refocused the interest of scientists toward drug combinations, ie, treating with TKIs and simultaneously targeting alternative survival mechanisms. One candidate target mechanism is autophagy, a cellular recycling process that acts as a cytoprotective shield in CML cells in response to TKI-induced stress and in other cancer cells surviving in an inhospitable microenvironment. On that basis, inhibition of autophagy has now become an exciting option for combination treatment in cancer, and clinical trials have been initiated in solid and hemopoietic tumors such as CML, chronic lymphocytic leukemia, and multiple myeloma. This review describes the biology of CML and elucidates how the molecular driver BCR-ABL led to the development of TKIs. We then discuss the molecular regulation of autophagy and the potential for autophagy inhibition as the next step in our attempt to tackle the problem of CML persistence to offer a curative option.
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: G Vignir
authors.initials: GV
authors.lastname: Helgason
authors.forename: Maria
authors.initials: M
authors.lastname: Karvela
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D053612:Janus Kinases / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050791:STAT Transcription Factors; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins