TY - JOUR
T1 - STAT3 mediates resistance to MEK inhibitor through microRNA miR-17
AU - Dai, Bingbing
AU - Meng, Jieru
AU - Peyton, Michael
AU - Girard, Luc
AU - Bornmann, William G.
AU - Ji, Lin
AU - Minna, John D.
AU - Fang, Bingliang
AU - Roth, Jack A.
PY - 2011/5/15
Y1 - 2011/5/15
N2 - 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-specificsmallmolecule inhibitor, or with STAT3-specific siRNAsensitized lung cancer cells toAZD6244 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-regulatedmicroRNAmiR-17 played a critical role inMEK 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 toMEK inhibitors by combining AZD6244 with STAT3 or miR-17 inhibitors.
AB - 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-specificsmallmolecule inhibitor, or with STAT3-specific siRNAsensitized lung cancer cells toAZD6244 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-regulatedmicroRNAmiR-17 played a critical role inMEK 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 toMEK inhibitors by combining AZD6244 with STAT3 or miR-17 inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=79956105175&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79956105175&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-3647
DO - 10.1158/0008-5472.CAN-10-3647
M3 - Article
C2 - 21444672
AN - SCOPUS:79956105175
SN - 0008-5472
VL - 71
SP - 3658
EP - 3668
JO - Cancer research
JF - Cancer research
IS - 10
ER -