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1.
Cancer Res ; 68(3): 664-73, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-18245465

RESUMEN

The classification of human tumors based on molecular criteria offers tremendous clinical potential; however, discerning critical and "druggable" effectors on a large scale will also require robust experimental models reflective of tumor genomic diversity. Here, we describe a comprehensive genomic analysis of 101 melanoma short-term cultures and cell lines. Using an analytic approach designed to enrich for putative "driver" events, we show that cultured melanoma cells encompass the spectrum of significant genomic alterations present in primary tumors. When annotated according to these lesions, melanomas cluster into subgroups suggestive of distinct oncogenic mechanisms. Integrating gene expression data suggests novel candidate effector genes linked to recurrent copy gains and losses, including both phosphatase and tensin homologue (PTEN)-dependent and PTEN-independent tumor suppressor mechanisms associated with chromosome 10 deletions. Finally, sample-matched pharmacologic data show that FGFR1 mutations and extracellular signal-regulated kinase (ERK) activation may modulate sensitivity to mitogen-activated protein kinase/ERK kinase inhibitors. Genetically defined cell culture collections therefore offer a rich framework for systematic functional studies in melanoma and other tumors.


Asunto(s)
Melanoma/genética , Melanoma/patología , Algoritmos , Línea Celular Tumoral , Aberraciones Cromosómicas , Deleción Cromosómica , Cromosomas Humanos Par 10 , Análisis por Conglomerados , ADN de Neoplasias/genética , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Perfilación de la Expresión Génica , Humanos , Pérdida de Heterocigocidad , Melanoma/enzimología , Melanoma/metabolismo , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfohidrolasa PTEN/genética , Polimorfismo de Nucleótido Simple , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Quinasas raf/genética
2.
Cancer Biol Ther ; 6(5): 661-7, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17495523

RESUMEN

Targeted cancer therapies impede cancer cell growth by inhibiting the function of activated oncogene products. Patients with non-small cell lung cancer and somatic mutations of EGFR can have a dramatic response to treatment with erlotinib and gefitinib; different somatic mutations are associated with different times to progression and survival. In this study, the relative and absolute potencies of two distinct EGFR tyrosine kinase inhibitors, erlotinib and an investigational irreversible inhibitor, HKI-272, were found to vary significantly in a panel of Ba/F3 cells transformed by representative EGFR somatic mutations. HKI-272 more potently inhibited the primary exon 20 insertion mutants, the secondary erlotinib-resistance mutants including T790M and many erlotinib-sensitive mutants including L858R. In contrast, erlotinib is a more potent inhibitor of the major exon 19 deletion mutants than is HKI-272. Analyses of EGFR autophosphorylation patterns confirmed the mutation-specific variation in relative potency of these tyrosine kinase inhibitors. Our finding that distinct EGFR inhibitors are more effective in vitro for different mutant forms of the protein suggests that tyrosine kinase inhibitor treatment could be tailored to specific EGFR mutations. More broadly, these results imply that the development and deployment of targeted therapies should focus on inhibition of specific cancer-causing mutations, not only on the mutated target.


Asunto(s)
Alelos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Quinolinas/farmacología , Sustitución de Aminoácidos , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cartilla de ADN/química , Clorhidrato de Erlotinib , Humanos , Ratones , Fragmentos de Péptidos/química , Fosforilación , Mutación Puntual , Células Precursoras de Linfocitos B/efectos de los fármacos , Células Precursoras de Linfocitos B/metabolismo , Retroviridae/genética , Eliminación de Secuencia
3.
Nat Genet ; 39(3): 347-51, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17293865

RESUMEN

Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.


Asunto(s)
Análisis Mutacional de ADN/métodos , Mutación , Neoplasias/genética , Oncogenes , Perfilación de la Expresión Génica , Genoma Humano , Genotipo , Humanos
4.
PLoS Med ; 3(12): e485, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17177598

RESUMEN

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.


Asunto(s)
Receptores ErbB/genética , Mutación Missense , Quinazolinas/farmacología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Cultivadas , Receptores ErbB/química , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Células 3T3 NIH , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Fosforilación , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Quinazolinas/química , Quinazolinas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección
5.
PLoS Med ; 2(11): e313, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16187797

RESUMEN

BACKGROUND: Somatic mutations in the kinase domain of the epidermal growth factor receptor tyrosine kinase gene EGFR are common in lung adenocarcinoma. The presence of mutations correlates with tumor sensitivity to the EGFR inhibitors erlotinib and gefitinib, but the transforming potential of specific mutations and their relationship to drug sensitivity have not been described. METHODS AND FINDINGS: Here, we demonstrate that EGFR active site mutants are oncogenic. Mutant EGFR can transform both fibroblasts and lung epithelial cells in the absence of exogenous epidermal growth factor, as evidenced by anchorage-independent growth, focus formation, and tumor formation in immunocompromised mice. Transformation is associated with constitutive autophosphorylation of EGFR, Shc phosphorylation, and STAT pathway activation. Whereas transformation by most EGFR mutants confers on cells sensitivity to erlotinib and gefitinib, transformation by an exon 20 insertion makes cells resistant to these inhibitors but more sensitive to the irreversible inhibitor CL-387,785. CONCLUSION: Oncogenic transformation of cells by different EGFR mutants causes differential sensitivity to gefitinib and erlotinib. Treatment of lung cancers harboring EGFR exon 20 insertions may therefore require the development of alternative kinase inhibition strategies.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Resistencia a Antineoplásicos/genética , Receptores ErbB/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Antineoplásicos/farmacología , Transformación Celular Neoplásica/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/biosíntesis , Receptores ErbB/genética , Clorhidrato de Erlotinib , Exones , Gefitinib , Terapia Genética , Humanos , Ratones , Ratones Desnudos , Mutación , Células 3T3 NIH , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/terapia , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinazolinas/farmacología , Factor de Transcripción STAT3/metabolismo , Proteínas Adaptadoras de la Señalización Shc , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src , Transfección , Ensayo de Tumor de Célula Madre
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