RESUMO
BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Serina-Treonina Quinases TOR/genética , Idoso , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Intervalo Livre de Doença , Cloridrato de Erlotinib/farmacologia , Feminino , Gefitinibe , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Resultado do TratamentoRESUMO
Cisplatin-based chemotherapy has long been the cornerstone of non-small cell lung cancer (NSCLC) management. However, median survival rarely exceeds 1 year. The identification of molecular markers can help to predict response, leading to a broad implementation of the new concept of customized chemotherapy. ERCC1 is an excision nuclease within the nucleotide excision repair pathway that forms a heterodimer with XPE As a unit, they execute the 5' incision into the DNA strand relative to the site of DNA damage. The 5' excision is the last of several steps that are specific to excision of a platinum DNA lesion. In mouse models, normal ERCC1 function is critical to normal aging and brain development. Numerous studies indicate that ERCC1 influences the repair of platinum DNA damage. We report here our accumulated experience of ERCC1 mRNA expression and outcome in cisplatin-treated NSCLC patients and the preliminary confirmatory data on a prospective ERCC1 mRNA customized docetaxel-cisplatin trial, in which low ERCC1 mRNA levels in the tumor correlate with significantly better response. ERCC1 is one of several proteins involved in the repairosome, where other DNA repair genes, such as BRCA1, are also central to cisplatin resistance.