Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer

James S. Duncan, Martin C. Whittle, Kazuhiro Nakamura, Amy N. Abell, Alicia A. Midland, Jon S. Zawistowski, Nancy L. Johnson, Deborah A. Granger, Nicole Vincent Jordan, David B. Darr, Jerry Usary, Pei Fen Kuan, David M. Smalley, Ben Major, Xiaping He, Katherine A. Hoadley, Bing Zhou, Norman E. Sharpless, Charles M. Perou, William Y. KimShawn M. Gomez, Xin Chen, Jian Jin, Stephen V. Frye, H. Shelton Earp, Lee M. Graves, Gary L. Johnson

Research output: Contribution to journalArticlepeer-review

517 Scopus citations

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.

Original languageEnglish
Pages (from-to)307-321
Number of pages15
JournalCell
Volume149
Issue number2
DOIs
StatePublished - Apr 13 2012

Fingerprint

Dive into the research topics of 'Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer'. Together they form a unique fingerprint.

Cite this