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Cell ; 149(2): 307-21, 2012 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-22500798

RESUMO

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.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , MAP Quinase Quinase 1/antagonistas & inibidores , Proteínas Quinases/genética , Proteoma/análise , Animais , Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Benzimidazóis/uso terapêutico , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Sorafenibe
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