RESUMEN
Mutations in the ERBB2 gene were recently found in approximately 2% of primary non-small cell lung cancer (NSCLC) specimens; however, little is known about the functional consequences and the relevance to responsiveness to targeted drugs for most of these mutations. Here, we show that the major lung cancer-derived ERBB2 mutants, including the most frequent mutation, A775insYVMA, lead to oncogenic transformation in a cellular assay. Murine cells transformed with these mutants were relatively resistant to the reversible epidermal growth factor receptor (EGFR) inhibitor erlotinib, resembling the resistant phenotype found in cells carrying the homologous mutations in exon 20 of EGFR. However, the same cells were highly sensitive to the irreversible dual-specificity EGFR/ERBB2 kinase inhibitor HKI-272, as were those overexpressing wild-type ERBB2. Finally, the NSCLC cell line, Calu-3, overexpressing wild-type ERBB2 owing to a high-level amplification of the ERBB2 gene were highly sensitive to HKI-272. These results provide a rationale for treatment of patients with ERBB2-mutant or ERBB2-amplified lung tumors with HKI-272.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Genes erbB-2 , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Receptores ErbB/antagonistas & inhibidores , Amplificación de Genes , Humanos , Neoplasias Pulmonares/enzimologíaRESUMEN
In recent years, the decrease in reported tuberculosis in the United States has been due almost entirely to a drop in the number of cases of pulmonary disease. There has been little change in the average number of extrapulmonary cases reported. A retrospective survey of extrapulmonary tuberculosis has shown that it differs from pulmonary tuberculosis with regard to sex and race distribution, diagnosing physician's speciality and proportion of cases bacteriologically confirmed. There is variation within extrapulmonary cases according to specific anatomic site with regard to the above characteristics as well as age distribution. These epidemiologic differences in tuberculosis of different sites are unexplained.