Send to

Choose Destination
Haematologica. 2017 Sep;102(9):1519-1529. doi: 10.3324/haematol.2016.163436. Epub 2017 Jun 8.

Combined targeting of STAT3 and STAT5: a novel approach to overcome drug resistance in chronic myeloid leukemia.

Author information

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria.
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.
Department of Radiation Therapy, Medical University of Vienna, Austria.
Department of Laboratory Medicine, Medical University of Vienna, Austria.
Children's Cancer Research Institute (CCRI), Vienna, Austria.
Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Institute of Drug Delivery Sciences, Sojo University, Kumamoto and BioDynamics Research Laboratory, Kumamoto, Japan.
Department of Chemistry, University of Toronto, Canada.
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Department of Pediatrics, Medical University of Vienna, Austria.


In chronic myeloid leukemia, resistance against BCR-ABL1 tyrosine kinase inhibitors can develop because of BCR-ABL1 mutations, activation of additional pro-oncogenic pathways, and stem cell resistance. Drug combinations covering a broad range of targets may overcome resistance. CDDO-Me (bardoxolone methyl) is a drug that inhibits the survival of leukemic cells by targeting different pro-survival molecules, including STAT3. We found that CDDO-Me inhibits proliferation and survival of tyrosine kinase inhibitor-resistant BCR-ABL1+ cell lines and primary leukemic cells, including cells harboring BCR-ABL1T315I or T315I+ compound mutations. Furthermore, CDDO-Me was found to block growth and survival of CD34+/CD38- leukemic stem cells (LSC). Moreover, CDDO-Me was found to produce synergistic growth-inhibitory effects when combined with BCR-ABL1 tyrosine kinase inhibitors. These drug-combinations were found to block multiple signaling cascades and molecules, including STAT3 and STAT5. Furthermore, combined targeting of STAT3 and STAT5 by shRNA and STAT5-targeting drugs also resulted in synergistic growth-inhibition, pointing to a new efficient concept of combinatorial STAT3 and STAT5 inhibition. However, CDDO-Me was also found to increase the expression of heme-oxygenase-1, a heat-shock-protein that triggers drug resistance and cell survival. We therefore combined CDDO-Me with the heme-oxygenase-1 inhibitor SMA-ZnPP, which also resulted in synergistic growth-inhibitory effects. Moreover, SMA-ZnPP was found to sensitize BCR-ABL1+ cells against the combination 'CDDO-Me+ tyrosine kinase inhibitor'. Together, combined targeting of STAT3, STAT5, and heme-oxygenase-1 overcomes resistance in BCR-ABL1+ cells, including stem cells and highly resistant sub-clones expressing BCR-ABL1T315I or T315I-compound mutations. Whether such drug-combinations are effective in tyrosine kinase inhibitor-resistant patients with chronic myeloid leukemia remains to be elucidated.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center