@article{031d931723cf42cb8e706cc9da1eddb9,
title = "Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer",
abstract = "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.",
author = "Duncan, {James S.} and Whittle, {Martin C.} and Kazuhiro Nakamura and Abell, {Amy N.} and Midland, {Alicia A.} and Zawistowski, {Jon S.} and Johnson, {Nancy L.} and Granger, {Deborah A.} and Jordan, {Nicole Vincent} and Darr, {David B.} and Jerry Usary and Kuan, {Pei Fen} and Smalley, {David M.} and Ben Major and Xiaping He and Hoadley, {Katherine A.} and Bing Zhou and Sharpless, {Norman E.} and Perou, {Charles M.} and Kim, {William Y.} and Gomez, {Shawn M.} and Xin Chen and Jian Jin and Frye, {Stephen V.} and Earp, {H. Shelton} and Graves, {Lee M.} and Johnson, {Gary L.}",
note = "Funding Information: This work was supported by NIH grants GM30324, U54CA156735, and DK37871, NCI Breast SPORE CA58223, Breast Cancer Research Fund, and the University Cancer Research Fund. N.V.J. and M.W. are supported by NIH training grants GM007040 and CA71341. J.D. was supported by CIHR postdoctoral fellowship. The authors also acknowledge support by the High-throughput Sequencing and Proteomics Cores. Kinome illustration reproduced courtesy of Cell Signaling Technology, Inc. ( http://www.cellsignal.com ). ",
year = "2012",
month = apr,
day = "13",
doi = "10.1016/j.cell.2012.02.053",
language = "English",
volume = "149",
pages = "307--321",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",
}