Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer

被引：581

作者：

Duncan, James S. ^{[1
]}

Whittle, Martin C. ^{[1
]}

Nakamura, Kazuhiro ^{[1
]}

Abell, Amy N. ^{[1
]}

Midland, Alicia A. ^{[2
]}

Zawistowski, Jon S. ^{[1
]}

Johnson, Nancy L. ^{[1
]}

Granger, Deborah A. ^{[1
]}

Jordan, Nicole Vincent ^{[1
]}

Darr, David B. ^{[3
]}

Usary, Jerry ^{[3
]}

Kuan, Pei-Fen ^{[4
]}

Smalley, David M. ^{[1
]}

Major, Ben ^{[5
]}

He, Xiaping ^{[3
]}

Hoadley, Katherine A. ^{[3
]}

Zhou, Bing ^{[3
,6
]}

Sharpless, Norman E. ^{[3
,6
]}

Perou, Charles M. ^{[3
]}

Kim, William Y. ^{[3
,6
]}

Gomez, Shawn M. ^{[2
]}

Chen, Xin ^{[7
]}

Jin, Jian ^{[7
]}

Frye, Stephen V. ^{[7
]}

Earp, H. Shelton ^{[1
,6
]}

Graves, Lee M. ^{[1
]}

Johnson, Gary L. ^{[1
]}

机构：

[1] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Dept Pharmacol, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Curriculum Bioinformat & Computat Biol, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA

[4] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Dept Biostat, Chapel Hill, NC 27599 USA

[5] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA

[6] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Dept Med, Chapel Hill, NC 27599 USA

[7] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA

来源：

CELL | 2012年 / 149卷 / 02期

关键词：

RESISTANCE; MYC; PHOSPHORYLATION; EXPRESSION; RECEPTOR; KINASES; TRIAL; HER2;

D O I：

10.1016/j.cell.2012.02.053

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple-negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs). RNAi knockdown of ERK or c-Myc mimicked RTK induction by MEK inhibitors, and prevention of proteasomal c-Myc degradation blocked kinome reprogramming. MEK inhibitor-induced RTK stimulation overcame MEK2 inhibition, but not MEK1 inhibition, reactivating ERK and producing drug resistance. The C3Tag GEMM for TNBC similarly induced RTKs in response to MEK inhibition. The inhibitor-induced RTK profile suggested a kinase inhibitor combination therapy that produced GEMM tumor apoptosis and regression where single agents were ineffective. This approach defines mechanisms of drug resistance, allowing rational design of combination therapies for cancer.

引用

页码：307 / 321

页数：15

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