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1.
Cell ; 150(6): 1107-20, 2012 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-22980975

RESUMEN

Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.


Asunto(s)
Adenocarcinoma/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Genes Relacionados con las Neoplasias , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares/genética , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Exoma , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Tasa de Mutación
2.
Nat Chem Biol ; 19(3): 301-310, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36302897

RESUMEN

Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A-SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A-SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.


Asunto(s)
Neoplasias , ARN de Transferencia de Leucina , Línea Celular Tumoral , Muerte Celular , Apoptosis , Biosíntesis de Proteínas
3.
J Biol Chem ; 295(11): 3431-3446, 2020 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-32005668

RESUMEN

Cytotoxic molecules can kill cancer cells by disrupting critical cellular processes or by inducing novel activities. 6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP) is a small molecule that kills cancer cells by generation of novel activity. DNMDP induces complex formation between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) and specifically kills cancer cells expressing elevated levels of these two proteins. Here, we examined the characteristics and covariates of the cancer cell response to DNMDP. On average, the sensitivity of human cancer cell lines to DNMDP is correlated with PDE3A expression levels. However, DNMDP could also bind the related protein, PDE3B, and PDE3B supported DNMDP sensitivity in the absence of PDE3A expression. Although inhibition of PDE3A catalytic activity did not account for DNMDP sensitivity, we found that expression of the catalytic domain of PDE3A in cancer cells lacking PDE3A is sufficient to confer sensitivity to DNMDP, and substitutions in the PDE3A active site abolish compound binding. Moreover, a genome-wide CRISPR screen identified the aryl hydrocarbon receptor-interacting protein (AIP), a co-chaperone protein, as required for response to DNMDP. We determined that AIP is also required for PDE3A-SLFN12 complex formation. Our results provide mechanistic insights into how DNMDP induces PDE3A-SLFN12 complex formation, thereby killing cancer cells with high levels of PDE3A and SLFN12 expression.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias/patología , Secuencia de Bases , Biomarcadores de Tumor/metabolismo , Sistemas CRISPR-Cas/genética , Dominio Catalítico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/química , Mutación del Sistema de Lectura/genética , Genoma , Heterocigoto , Humanos , Unión Proteica/efectos de los fármacos , Piridazinas/farmacología
4.
Int J Cancer ; 146(8): 2194-2200, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-31290142

RESUMEN

Somatic mutations of epidermal growth factor receptor (EGFR) occur in ~3% of colorectal cancer (CRC) patients. Here, through systematic functional screening of 21 recurrent EGFR mutations selected from public data sets, we show that 11 colon cancer-derived EGFR mutants (G63R, E114K, R165Q, R222C, S492R, P596L, K708R, E709K, G719S, G724S and L858R) are oncogenic and able to transform cells in a ligand-independent manner. We demonstrate that cellular transformation by these mutants requires receptor dimerization. Importantly, the EGF-induced and constitutive oncogenic potential of these EGFR mutants are inhibited by cetuximab or panitumumab in vivo and in vitro. Taken together, we propose that a subset of EGFR mutations can serve as genomic predictors for response to anti-EGFR antibodies and that metastatic CRC patients with such mutations may benefit from these drugs as part of the first-line therapy.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Cetuximab/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Panitumumab/farmacología , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Animales , Antineoplásicos Inmunológicos/farmacología , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Dimerización , Receptores ErbB/genética , Receptores ErbB/inmunología , Receptores ErbB/metabolismo , Células HT29 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Terapia Molecular Dirigida , Mutación , Células 3T3 NIH , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Nature ; 506(7488): 371-5, 2014 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-24390348

RESUMEN

Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.


Asunto(s)
Genoma Humano/genética , Mutación/genética , Neoplasias del Cuello Uterino/genética , Adenocarcinoma/genética , Adenocarcinoma/virología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virología , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Subunidad beta del Factor de Unión al Sitio Principal/genética , Variaciones en el Número de Copia de ADN/genética , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Proteína p300 Asociada a E1A/genética , Exoma/genética , Proteínas F-Box/genética , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Genómica , Antígenos HLA-B/genética , Humanos , Proteína Quinasa 1 Activada por Mitógenos/genética , Factor 2 Relacionado con NF-E2/genética , Papillomaviridae/genética , Papillomaviridae/fisiología , Infecciones por Papillomavirus/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ets , Receptor ErbB-2/genética , Factores de Transcripción/genética , Transcriptoma/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Neoplasias del Cuello Uterino/virología , Integración Viral/genética
7.
Nat Chem Biol ; 12(2): 102-8, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26656089

RESUMEN

High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the gene PDE3A, encoding phosphodiesterase 3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells, whereas others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggestive of a neomorphic activity. Coexpression of SLFN12 with PDE3A correlates with DNMDP sensitivity, whereas depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Citotoxinas/farmacología , Neoplasias/terapia , Piridazinas/química , Piridazinas/farmacología , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citotoxinas/química , Citotoxinas/aislamiento & purificación , Sistemas de Liberación de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Genómica , Humanos , Immunoblotting
8.
Nature ; 488(7409): 106-10, 2012 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-22820256

RESUMEN

Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, ß-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic ß-catenin signalling in medulloblastoma.


Asunto(s)
Neoplasias Cerebelosas/genética , Exoma/genética , Genoma Humano/genética , Meduloblastoma/genética , Mutación/genética , Neoplasias Cerebelosas/clasificación , Niño , ARN Helicasas DEAD-box/química , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , ADN Helicasas/química , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Proteínas Hedgehog/metabolismo , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas con Dominio LIM/genética , Meduloblastoma/clasificación , Modelos Moleculares , Proteínas de Neoplasias/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Receptores Patched , Receptor Patched-1 , Regiones Promotoras Genéticas/genética , Estructura Terciaria de Proteína/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Superficie Celular/genética , Proteínas Represoras/genética , Transducción de Señal , Factores de Transcripción TCF/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
10.
Nature ; 463(7283): 899-905, 2010 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-20164920

RESUMEN

A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Dosificación de Gen/genética , Neoplasias/genética , Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Amplificación de Genes/genética , Genómica , Humanos , Familia de Multigenes/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Neoplasias/clasificación , Neoplasias/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Transducción de Señal , Proteína bcl-X/genética
11.
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
12.
Cancer Cell ; 11(3): 217-27, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17349580

RESUMEN

Mutations in the EGFR kinase are a cause of non-small-cell lung cancer. To understand their mechanism of activation and effects on drug binding, we studied the kinetics of the L858R and G719S mutants and determined their crystal structures with inhibitors including gefitinib, AEE788, and a staurosporine. We find that the mutations activate the kinase by disrupting autoinhibitory interactions, and that they accelerate catalysis as much as 50-fold in vitro. Structures of inhibitors in complex with both wild-type and mutant kinases reveal similar binding modes for gefitinib and AEE788, but a marked rotation of the staurosporine in the G719S mutant. Strikingly, direct binding measurements show that gefitinib binds 20-fold more tightly to the L858R mutant than to the wild-type enzyme.


Asunto(s)
Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Receptores ErbB/química , Neoplasias Pulmonares/metabolismo , Modelos Moleculares , Mutación , Sitios de Unión , Cristalografía por Rayos X , Activación Enzimática , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Gefitinib , Humanos , Lapatinib , Conformación Proteica , Estructura Terciaria de Proteína , Purinas/química , Quinazolinas/química , Estaurosporina/análogos & derivados , Estaurosporina/química
13.
Proc Natl Acad Sci U S A ; 109(36): 14476-81, 2012 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-22908275

RESUMEN

We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity. Five of these genes failed to score in transformation assays; however, novel recurring extracellular domain mutations of the receptor tyrosine kinase gene ERBB2 were potently oncogenic. These ERBB2 extracellular domain mutants were activated by two distinct mechanisms, characterized by elevated C-terminal tail phosphorylation or by covalent dimerization mediated by intermolecular disulfide bond formation. These distinct mechanisms of receptor activation converged upon tyrosine phosphorylation of cellular proteins, impacting cell motility. Survival of Ba/F3 cells transformed to IL-3 independence by the ERBB2 extracellular domain mutants was abrogated by treatment with small-molecule inhibitors of ERBB2, raising the possibility that patients harboring such mutations could benefit from ERBB2-directed therapy.


Asunto(s)
Adenocarcinoma/enzimología , Neoplasias Pulmonares/enzimología , Mutación/genética , Receptor ErbB-2/genética , Adenocarcinoma/genética , Adenocarcinoma del Pulmón , Alelos , Animales , Movimiento Celular/fisiología , Clonación Molecular , Cartilla de ADN/genética , Dimerización , Immunoblotting , Neoplasias Pulmonares/genética , Ratones , Células 3T3 NIH , Fosforilación , Estructura Terciaria de Proteína/genética , Retroviridae , Espectrometría de Masas en Tándem
14.
Mol Cancer ; 13: 141, 2014 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-24894453

RESUMEN

BACKGROUND: Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear. FINDINGS: We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors. CONCLUSION: The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy.


Asunto(s)
Adenocarcinoma/genética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Colorrectales/genética , Receptores ErbB/genética , Mutación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Antineoplásicos/uso terapéutico , Cetuximab , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Multimerización de Proteína , Estructura Terciaria de Proteína
15.
Nature ; 455(7215): 975-8, 2008 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-18923525

RESUMEN

Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.


Asunto(s)
Mutación/genética , Neuroblastoma/genética , Neuroblastoma/terapia , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Alelos , Quinasa de Linfoma Anaplásico , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Activación Enzimática/genética , Genoma Humano/genética , Humanos , Hibridación Fluorescente in Situ , Etiquetado Corte-Fin in Situ , Ratones , Neuroblastoma/enzimología , Neuroblastoma/patología , Polimorfismo de Nucleótido Simple/genética , Estructura Terciaria de Proteína/genética , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas Receptoras , Análisis de Secuencia de ADN
16.
Nature ; 455(7216): 1069-75, 2008 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-18948947

RESUMEN

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.


Asunto(s)
Adenocarcinoma Bronquioloalveolar/genética , Neoplasias Pulmonares/genética , Mutación/genética , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Masculino , Proto-Oncogenes/genética
17.
Cell Chem Biol ; 31(6): 1039-1043, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38906108

RESUMEN

Velcrins are molecular glues that induce complex formation between PDE3A and SLFN12. The PDE3A-SLFN12 complex activates the SLFN12 RNase, resulting in cleavage of the specific substrate, tRNA-Leu-TAA, global inhibition of translation, and death of cells expressing sufficient levels of both proteins. Here, unanswered questions about the mechanism of action and therapeutic promise of velcrin compounds are discussed.


Asunto(s)
Endorribonucleasas , Humanos , Endorribonucleasas/metabolismo , Proteínas Bacterianas , Endodesoxirribonucleasas , Proteínas Asociadas a CRISPR
18.
Nat Med ; 12(7): 852-5, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16799556

RESUMEN

The sensitivity of conventional DNA sequencing in tumor biopsies is limited by stromal contamination and by genetic heterogeneity within the cancer. Here, we show that microreactor-based pyrosequencing can detect rare cancer-associated sequence variations by independent and parallel sampling of multiple representatives of a given DNA fragment. This technology can thereby facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies.


Asunto(s)
Mapeo Cromosómico/métodos , ADN de Neoplasias/genética , Mutación , Neoplasias/genética , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Neoplasias/diagnóstico , Sensibilidad y Especificidad
19.
Nature ; 450(7171): 893-8, 2007 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-17982442

RESUMEN

Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.


Asunto(s)
Adenocarcinoma/genética , Genoma Humano/genética , Neoplasias Pulmonares/genética , Neoplasias/genética , Línea Celular Tumoral , Deleción Cromosómica , Cromosomas Humanos Par 14/genética , Amplificación de Genes/genética , Genómica , Genotipo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Pérdida de Heterocigocidad/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , Proto-Oncogenes Mas , Interferencia de ARN , Factor Nuclear Tiroideo 1 , Factores de Transcripción/genética
20.
Proc Natl Acad Sci U S A ; 106(2): 474-9, 2009 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-19122144

RESUMEN

Mutations in the HER2 kinase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2(YVMA)) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2(YVMA) is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2(YVMA) transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Adenoescamoso/tratamiento farmacológico , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/farmacología , Receptor ErbB-2/genética , Sirolimus/farmacología , Afatinib , Animales , Evaluación Preclínica de Medicamentos , Ratones , Mutación , Fosforilación/efectos de los fármacos , Quinazolinas/uso terapéutico , Receptor ErbB-2/fisiología , Transducción de Señal/efectos de los fármacos , Sirolimus/uso terapéutico
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