title: STAT3 mediates resistance to MEK inhibitor through microRNA miR-17.
abstract: AZD6244 is a small molecule inhibitor of the MEK (MAP/ERK kinase) pathway currently in clinical trials. However, the mechanisms mediating intrinsic resistance to MEK inhibition are not fully characterized. To define molecular mechanisms of MEK inhibitor resistance, we analyzed responses of 38 lung cancer cell lines following AZD6244 treatment and their genome-wide gene expression profiles and identified a panel of genes correlated with sensitivity or resistance to AZD6244 treatment. In particular, ingenuity pathway analysis revealed that activation of the STAT3 pathway was associated with MEK inhibitor resistance. Inhibition of this pathway by JSI-124, a STAT3-specific small molecule inhibitor, or with STAT3-specific siRNA sensitized lung cancer cells to AZD6244 and induced apoptosis. Moreover, combining a STAT3 inhibitor with AZD6244 induced expression of BIM and PARP cleavage, whereas activation of the STAT3 pathway inhibited BIM expression and elicited resistance to MEK inhibitors. We found that the STAT3-regulated microRNA miR-17 played a critical role in MEK inhibitor resistance, such that miR-17 inhibition sensitized resistant cells to AZD6244 by inducing BIM and PARP cleavage. Together, these results indicated that STAT3-mediated overexpression of miR-17 blocked BIM expression and caused resistance to AZD6244. Our findings suggest novel approaches to overcome resistance to MEK inhibitors by combining AZD6244 with STAT3 or miR-17 inhibitors.
authors: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. bdai@mdanderson.org
authors: Bingbing
authors: B
authors: Dai
authors: Jieru
authors: J
authors: Meng
authors: Michael
authors: M
authors: Peyton
authors: Luc
authors: L
authors: Girard
authors: William G
authors: WG
authors: Bornmann
authors: Lin
authors: L
authors: Ji
authors: John D
authors: JD
authors: Minna
authors: Bingliang
authors: B
authors: Fang
authors: Jack A
authors: JA
authors: Roth
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: C524941:MIRN17 microRNA, human; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D020929:Mitogen-Activated Protein Kinase Kinases