Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance.
Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenvironment of CML and is a rich source of both soluble factors and extracellular matrices, which may influence drug response. To address the influence of the bone marrow microenvironment on imatinib mesylate sensitivity, we used an in vitro bone marrow stroma model. Our data show culturing K562 cells, in bone marrow stroma-derived conditioned medium (CM), is sufficient to cause resistance to BCR-ABL inhibitors. Drug resistance correlated with increased pTyrStat3, whereas no increases in pTyrStat5 was noted. Moreover, resistance was associated with increased levels of the Stat3 target genes Bcl-xl, Mcl-1, and survivin. Finally, reducing Stat3 levels with small interfering RNA sensitized K562 cells cultured in CM to imatinib mesylate-induced cell death. Importantly, Stat3 dependency was specific for cells grown in CM, as reducing Stat3 levels in regular growth conditions had no effect on imatinib mesylate sensitivity. Together, these data support a novel mechanism of BCR-ABL-independent imatinib mesylate resistance and provides preclinical rationale for using Stat3-inhibitors to increase the efficacy of imatinib mesylate within the context of the bone marrow microenvironment.
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33613, USA.
Nadine N
NN
Bewry
Rajesh R
RR
Nair
Michael F
MF
Emmons
David
D
Boulware
Javier
J
Pinilla-Ibarz
Lori A
LA
Hazlehurst
D001549:Benzamides; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology; D019000:Phosphotyrosine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology
D001549:Benzamides; D017077:Culture Media, Conditioned; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D013844:Thiazoles; D019000:Phosphotyrosine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib