TY - JOUR
T1 - Combined targeting of STAT3 and STAT5
T2 - A novel approach to overcome drug resistance in chronic myeloid leukemia
AU - Gleixner, Karoline V.
AU - Schneeweiss, Mathias
AU - Eisenwort, Gregor
AU - Berger, Daniela
AU - Herrmann, Harald
AU - Blatt, Katharina
AU - Greiner, Georg
AU - Byrgazov, Konstantin
AU - Hoermann, Gregor
AU - Konopleva, Marina
AU - Waliul, Islam
AU - Cumaraswamy, Abbarna A.
AU - Gunning, Patrick T.
AU - Maeda, Hiroshi
AU - Moriggl, Richard
AU - Deininger, Michael
AU - Lion, Thomas
AU - Andreeff, Michael
AU - Valent, Peter
N1 - Funding Information:
This study was supported by Austrian Science Fund (FWF), grants F4701-B20 and F4704-B20 (to PV), F4705-B20 (to TL) and F4707-B20 (to RM) and by a Grant-in-Aid from the Ministry of Welfare, Health and Labor of Japan, (201220042), and A-STEP for cancer grant (AS242Z01542Q) from the Japan Science and Technology Agency (to HM).
Publisher Copyright:
© 2017 Ferrata Storti Foundation.
PY - 2017/8/31
Y1 - 2017/8/31
N2 - 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 growthinhibitory 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.
AB - 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 growthinhibitory 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85029584654&partnerID=8YFLogxK
U2 - 10.3324/haematol.2016.163436
DO - 10.3324/haematol.2016.163436
M3 - Article
C2 - 28596283
AN - SCOPUS:85029584654
SN - 0390-6078
VL - 102
SP - 1519
EP - 1529
JO - Haematologica
JF - Haematologica
IS - 9
ER -