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 leukaemia (CML) represents the most successful example of targeted therapy in human cancer. However, leukaemic stem cells (LSCs) are insensitive to tyrosine kinase inhibitors (TKIs) and contribute to disease persistence by representing a reservoir of selfrenewing cells that replenish the disease upon drug discontinuation. This has refocused the interest of scientists towards drug combinations i.e. 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 haemopoietic tumours such as CML, chronic lymphocytic leukaemia (CLL) 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.

Autophagy in blood cancers: biological role and therapeutic implications

“…51 In turn, autophagy promotes survival and leukemogenic potential of CML stem cells 30,52 which are insensitive to TKIs 53,54 and are considered to be responsible for disease relapses after TKI discontinuation. 50 We demonstrated that suppression of autophagy, using either pharmacological inhibitors or silencing of essential autophagy genes, enhanced cell death induced by imatinib in cell lines and primary CML cells. 38,50 Moreover, the combination of imatinib, nilotinib, or dasatinib with CQ-mediated autophagy inhibition, resulted in near complete elimination of phenotypically and functionally defined CML stem cells.…”

“…50 We demonstrated that suppression of autophagy, using either pharmacological inhibitors or silencing of essential autophagy genes, enhanced cell death induced by imatinib in cell lines and primary CML cells. 38,50 Moreover, the combination of imatinib, nilotinib, or dasatinib with CQ-mediated autophagy inhibition, resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Additional experiments have meanwhile confirmed the potential of autophagy inhibition as a strategy to strengthen the activity of TKIs in CML.…”

“…Of particular interest in this context is the use of autophagy inhibitors CML. Tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib or nilotinib, that currently represent the gold standard of CML treatment, 50 stimulate autophagy in CML cells, likely through inhibition of the PI3K-AKTmTORC1 axis. 51 In turn, autophagy promotes survival and leukemogenic potential of CML stem cells 30,52 which are insensitive to TKIs 53,54 and are considered to be responsible for disease relapses after TKI discontinuation.…”

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

“…An exciting development for the use of chloroquine is in combination with the tyrosine kinase inhibitor, imatinib, which primarily targets the constitutively active chimaeric BCR-ABL protein commonly associated with chronic myeloid leukaemia (CML) and to a lesser extent chronic lymphocytic leukaemia and acute lymphoblastic leukaemia (Helgason et al, 2011). Bellodi et al (2009) previously observed an increase in autophagy levels in CML stem cells treated with imatinib, and the inhibition of autophagy by chloroquine or ATG5/ATG7 knockdown was able to enhance imatinib-induced cell death.…”

Study on the treatment of the p15 gene combined with Bcr-abl-specific siRNA and STI571 for chronic myeloid leukemia

“…About 90% CML patients have the distinctive Ph chromosome in their leukemic cells (Helgason et al, 2011;Leonetti et al, 2011), which is formed by the mutual translocation of the 3 zone 4 band in the long arm of chromosome 9 (9q34) and the 1 zone 1 band in the long arm of chromosome 22 (22q11), t (9; 22) (q34; q11). In addition, the proto-oncogene c-abl at 9q34 id broken at the 5'-end of its second exon, and shifted to 22q11 of the bcr gene at the 3'-end of the second or third exon (M-bcr) for rearrangement, forming the fusion gene bcr/abl.…”