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Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer.
Cell ; 149(2): 307-21, 2012 Apr 13.
Article em En | MEDLINE | ID: mdl-22500798
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

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Quinases / Neoplasias da Mama / Resistencia a Medicamentos Antineoplásicos / Proteoma / MAP Quinase Quinase 1 Limite: Animals / Female / Humans / Male Idioma: En Revista: Cell Ano de publicação: 2012 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Quinases / Neoplasias da Mama / Resistencia a Medicamentos Antineoplásicos / Proteoma / MAP Quinase Quinase 1 Limite: Animals / Female / Humans / Male Idioma: En Revista: Cell Ano de publicação: 2012 Tipo de documento: Article País de afiliação: Estados Unidos