Targeting the Autophagy Pathways in Chronic Myeloid Leukemia Stem Cells

Targeting the Autophagy Pathways in CML Stem Cells

 

CML is charaterised by the Philadelphia (Ph) chromosome and BCR-ABL kinase. Aberrant kinase activity results in activation of a number of signalling pathways that include PI3K/AKT/mTOR, leading to suppression of autophagy and mimicking the effects of growth factor stimulation. The introduction of kinase inhibitors, for example imatinib mesylate (IM), some 13 years ago has revolutionised the treatment of CML with the majority of patients entering sustained remissions. Two clinical issues that remain for CML patients are the fact that responding patients harbour residual disease thought to result from IM insensitive CML stem cells and the development of acquired drug resistance through ABL kinase domain mutations. We have previously demonstrated that kinase inhibitors, such as IM, induce autophagy in Ph+ cells by suppressing BCR-ABL kinase activity and downstream pathways (Bellodi C et al JCI 2009, 119: 1109; Helgason GV Blood 2011, 118: 2035). Of critical importance we have shown that in CML stem and progenitor cells IM-induced autophagy provides a survival mechanism. The addition of chloroquine to inhibit IM-induced autophagy leads to greatly enhanced cell kill, including the CML stem cell population. This pre-clinical work has now been progressed to a clinical trial – CHOICES – in which CML patients with residual disease on IM are randomised to continue IM or to have hydroxychloroquine added to IM for 12 months. The primary endpoints of the trial are safety and efficacy and patients in both treatment groups are being followed with pharmacokinetic and pharmacodynamic endpoints (www.clinicaltrials.gov). For cases of CML exhibiting acquired IM-resistance we are investigating the efficacy of inhibitors of BCR-ABL downstream signalling, for example dual PI3K/mTOR inhibitors, to determine firstly if these drugs induce cell death in the CML stem and progenitor cells, secondly if they induce protective autophagy and thirdly if they synergise with hydroxychloroquine or alternative approaches to inhibit autophagy to enhance leukaemic cell kill. These laboratory and clinical approaches will be discussed.