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; K. A. Hoadley; Bing Zhou; Norman E. Sharpless; Charles M. Perou; William Y. Kim; Gary L. Johnson

doi:10.1016/j.cell.2012.02.053

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, K. A. Hoadley, Bing Zhou, Norman E. Sharpless, Charles M. Perou, William Y. KimGary L. Johnson

Research output: Contribution to journal › Article › peer-review

598 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 language	English
Pages (from-to)	307-321
Number of pages	15
Journal	Cell
Volume	149
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2012.02.053
State	Published - Apr 13 2012

Keywords

Animals
Antineoplastic Agents/therapeutic use
Benzenesulfonates/therapeutic use
Benzimidazoles/therapeutic use
Breast Neoplasms/drug therapy
Disease Models, Animal
Drug Resistance, Neoplasm
Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors
Female
Gene Expression Regulation, Neoplastic
Humans
MAP Kinase Kinase 1/antagonists & inhibitors
Male
Mice
Niacinamide/analogs & derivatives
Phenylurea Compounds
Protein Kinase Inhibitors/therapeutic use
Protein Kinases/genetics
Proteome/analysis
Proto-Oncogene Proteins c-myc/metabolism
Pyridines/therapeutic use
Receptor Protein-Tyrosine Kinases/genetics
Sorafenib

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2012.02.053

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Duncan, J. S., Whittle, M. C., Nakamura, K., Abell, A. N., Midland, A. A., Zawistowski, J. S., Johnson, N. L., Granger, D. A., Jordan, N. V., Darr, D. B., Usary, J., Kuan, P. F., Smalley, D. M., Major, B., He, X., Hoadley, K. A., Zhou, B., Sharpless, N. E., Perou, C. M., ... Johnson, G. L. (2012). Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell, 149(2), 307-321. https://doi.org/10.1016/j.cell.2012.02.053

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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.",

keywords = "Animals, Antineoplastic Agents/therapeutic use, Benzenesulfonates/therapeutic use, Benzimidazoles/therapeutic use, Breast Neoplasms/drug therapy, Disease Models, Animal, Drug Resistance, Neoplasm, Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors, Female, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Kinase 1/antagonists & inhibitors, Male, Mice, Niacinamide/analogs & derivatives, Phenylurea Compounds, Protein Kinase Inhibitors/therapeutic use, Protein Kinases/genetics, Proteome/analysis, Proto-Oncogene Proteins c-myc/metabolism, Pyridines/therapeutic use, Receptor Protein-Tyrosine Kinases/genetics, Sorafenib",

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, {K. A.} and Bing Zhou and Sharpless, {Norman E.} and Perou, {Charles M.} and Kim, {William Y.} and Johnson, {Gary L.}",

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",

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Duncan, JS, Whittle, MC, Nakamura, K, Abell, AN, Midland, AA, Zawistowski, JS, Johnson, NL, Granger, DA, Jordan, NV, Darr, DB, Usary, J, Kuan, PF, Smalley, DM, Major, B, He, X, Hoadley, KA, Zhou, B, Sharpless, NE, Perou, CM, Kim, WY & Johnson, GL 2012, 'Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer', Cell, vol. 149, no. 2, pp. 307-321. https://doi.org/10.1016/j.cell.2012.02.053

TY - JOUR

T1 - Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer

AU - Duncan, James S.

AU - Whittle, Martin C.

AU - Nakamura, Kazuhiro

AU - Abell, Amy N.

AU - Midland, Alicia A.

AU - Zawistowski, Jon S.

AU - Johnson, Nancy L.

AU - Granger, Deborah A.

AU - Jordan, Nicole Vincent

AU - Darr, David B.

AU - Usary, Jerry

AU - Kuan, Pei Fen

AU - Smalley, David M.

AU - Major, Ben

AU - He, Xiaping

AU - Hoadley, K. A.

AU - Zhou, Bing

AU - Sharpless, Norman E.

AU - Perou, Charles M.

AU - Kim, William Y.

AU - Johnson, Gary L.

PY - 2012/4/13

Y1 - 2012/4/13

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents/therapeutic use

KW - Benzenesulfonates/therapeutic use

KW - Benzimidazoles/therapeutic use

KW - Breast Neoplasms/drug therapy

KW - Disease Models, Animal

KW - Drug Resistance, Neoplasm

KW - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - MAP Kinase Kinase 1/antagonists & inhibitors

KW - Male

KW - Mice

KW - Niacinamide/analogs & derivatives

KW - Phenylurea Compounds

KW - Protein Kinase Inhibitors/therapeutic use

KW - Protein Kinases/genetics

KW - Proteome/analysis

KW - Proto-Oncogene Proteins c-myc/metabolism

KW - Pyridines/therapeutic use

KW - Receptor Protein-Tyrosine Kinases/genetics

KW - Sorafenib

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U2 - 10.1016/j.cell.2012.02.053

DO - 10.1016/j.cell.2012.02.053

M3 - Article

C2 - 22500798

SN - 0092-8674

VL - 149

SP - 307

EP - 321

JO - Cell

JF - Cell

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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