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Targeting STATs to overcome drug resistance in chronic myeloid leukemia

In chronic myeloid leukemia BCR-ABL1 mutations and activation of additional pro-oncogenic pathways  cause therapy resistance. Drug combinations covering a broad range of targets may overcome resistance.We investigated a compound that inhibits proliferation and survival of tyrosine kinase inhibitor-resistant BCR-ABL1+ cell lines. Succesful drug-combinations blocked multiple signalling 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. Combined targeting of STAT3, STAT5, and heme-oxygenase-1 overcomes resistance in cell lines and whether such drug-combinations are effective in tyrosine kinase inhibitor-resistant patients with chronic myeloid leukemia should be elucidated.

These findings result from an international collaboration based on SFB F47 funded by the Austrian Science Fund and were now reported in Haematologica.