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Blood. 2011 Aug 25;118(8):2035-43. doi: 10.1182/blood-2011-01-330621. Epub 2011 Jun 21.

Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML.

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  • 1Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

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.

PMID:
21693757
[PubMed - indexed for MEDLINE]
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