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1.
Ann Oncol ; 33(10): 1029-1040, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35872166

RESUMEN

BACKGROUND: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASMUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never-smoking status and is largely uncharacterized. PATIENTS AND METHODS: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype. RESULTS: Of 2327 patients with KRAS-mutated (KRASMUT) NSCLC, 15% (n = 354) harbored KRASG12D. Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRASG12D had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1-based therapies, KRASG12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRASnon-G12D. CONCLUSIONS: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Factores de Transcripción Forkhead , Genómica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Receptor de Muerte Celular Programada 1 , Proteínas Proto-Oncogénicas p21(ras)/genética
3.
Ann Oncol ; 31(6): 807-814, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32171752

RESUMEN

BACKGROUND: Programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) is the primary clinically-available biomarker of response to immunotherapy in non-small-cell lung cancer (NSCLC), but factors associated with PD-L1 expression are not well understood. MATERIALS AND METHODS: Consecutive nonsquamous NSCLCs with successful PD-L1 assessment and targeted next-generation sequencing were included in this retrospective study. Clinicopathological characteristics, gene mutations, and copy number changes in gene and chromosomal arms were compared among three PD-L1 expression groups: negative (TPS < 1%), low (TPS 1%-49%), and high (TPS ≥ 50%). A Q-value <0.25 was considered significant after multiple comparisons correction. RESULTS: A total of 909 nonsquamous NSCLCs were included. High PD-L1 expression compared with low and negative PD-L1 expression was associated with increased tobacco exposure (median pack-years: 25 versus 20 versus 20, respectively; P = 0.01), advanced stage at diagnosis (76% versus 67% versus 61% with advanced stage of disease, respectively; P < 0.001), and higher tumor mutational burden (TMB) (median 12.2 versus 10.6 versus 10.6 mutations/megabase, respectively; P < 0.001). Negative PD-L1 expression when compared with high PD-L1 expression was associated with: mutations in STK11 (19% versus 5%; Q < 0.001), EGFR (22% versus 11%; Q < 0.001), CTNNB1 (4.3% versus 0.4%; Q = 0.04), APC (5% versus 1%; Q = 0.17), and SMARCA4 (9% versus 4%; Q = 0.20); copy number loss of CD274 (PD-L1, 28% versus 6%; Q < 0.001), PDCD1LG2 (PD-L2, 28% versus 6%; Q < 0.001), and JAK2 genes (27% versus 7%; Q < 0.001), loss of chromosomal arm 9p (23% versus 10%; Q = 0.04), and gain of 1q (46% versus 21%; Q < 0.001). High PD-L1 expression compared with negative PD-L1 expression was associated with copy number gain of CD274 (11% versus 3%; Q = 0.01) and PDCD1LG2 (11% versus 3%; Q = 0.01). NSCLCs with CD274 loss, compared with those without loss, had a lower response rate (23% versus 9%; P = 0.006) and shorter progression-free survival (3.3 versus 2.0 months; P = 0.002) on immunotherapy. CONCLUSIONS: PD-L1 expression is associated with specific genomic alterations and clinicopathologic characteristics in nonsquamous NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Apoptosis , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Genómica , Humanos , Ligandos , Neoplasias Pulmonares/genética , Estudios Retrospectivos
4.
Gynecol Oncol ; 134(3): 599-606, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24995579

RESUMEN

PURPOSE: Our previously reported 29-gene expression signature identified an aggressive subgroup of endometrial cancer patients with PI3K activation. We here wanted to validate these findings by independent patient series. PATIENTS AND METHODS: The 29-gene expression signature was assessed in fresh frozen tumor tissue from 280 primary endometrial carcinomas (three independent cohorts), 19 metastatic lesions and in 333 primary endometrial carcinomas using TCGA data, and expression was related to clinico-pathologic features and survival. The 29-gene signature was assessed by real-time quantitative PCR, DNA oligonucleotide microarrays, or RNA sequencing. PI3K alterations were assessed by immunohistochemistry, DNA microarrays, DNA sequencing, SNP arrays or fluorescence in situ hybridization. A panel of markers of epithelial-mesenchymal transition (EMT) was also correlated to the 29-gene signature score. RESULTS: High 29-gene Endometrial Carcinoma Recurrence Score (ECARS) values consistently validated to identify patients with aggressive clinico-pathologic phenotype and reduced survival. Within the presumed favorable subgroups of low grade, endometrioid tumors confined to the uterus, high ECARS still predicted a poor prognosis. The score was higher in metastatic compared to primary lesions (P<0.001) and was significantly associated with potential measures of PI3K activation, markers of EMT and vascular invasion as an indicator of metastatic spread (all P<0.001). CONCLUSIONS: ECARS validates to identify aggressive endometrial carcinomas in multiple, independent patients cohorts. The higher signature score in metastatic compared to primary lesions, and the potential link to PI3K activation and EMT, support further studies of ECARS in relation to response to PI3K and EMT inhibitors in clinical trials of metastatic endometrial carcinoma.


Asunto(s)
Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Transición Epitelial-Mesenquimal , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Fosfatidilinositol 3-Quinasas/genética , Biomarcadores de Tumor , Neoplasias Endometriales/epidemiología , Femenino , Humanos
5.
Oncogene ; 33(45): 5295-302, 2014 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-24909177

RESUMEN

Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss  of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer.


Asunto(s)
ARN Helicasas DEAD-box/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Mutación , Blastoma Pulmonar/genética , Ribonucleasa III/genética , Proteína p53 Supresora de Tumor/genética , Secuencia de Bases , Cromosomas Humanos Par 5/genética , ARN Helicasas DEAD-box/metabolismo , Variaciones en el Número de Copia de ADN , Exoma/genética , Femenino , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , MicroARNs/química , Conformación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Blastoma Pulmonar/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleasa III/metabolismo , Análisis de Secuencia de ADN/métodos , Proteína p53 Supresora de Tumor/metabolismo
6.
Oncogene ; 33(35): 4418-23, 2014 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-24469055

RESUMEN

Lung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic mutations in RTK/RAS pathway members KRAS, EGFR, BRAF and ERBB2, and translocations involving ALK, RET and ROS1. Identification of these oncogenic events has transformed the treatment of lung adenocarcinoma via application of therapies targeted toward specific genetic lesions in stratified patient populations. However, such mutations have been reported in only ∼55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy are involved in the remaining cases. Here we report somatic mutations in the small GTPase gene RIT1 in ∼2% of lung adenocarcinoma cases that cluster in a hotspot near the switch II domain of the protein. RIT1 switch II domain mutations are mutually exclusive with all other known lung adenocarcinoma driver mutations. Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo, which can be reversed by combined PI3K and MEK inhibition. These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors.


Asunto(s)
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Proteínas ras/genética , Proteínas ras/metabolismo , Adenocarcinoma/patología , Animales , Antineoplásicos/farmacología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/patología , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Desnudos , Mutación , Células 3T3 NIH , Neoplasias Experimentales , Células PC12 , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Ratas , Estados Unidos , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Oncogene ; 29(11): 1588-97, 2010 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-19966866

RESUMEN

Germline TSC1 or TSC2 mutations cause tuberous sclerosis complex (TSC), a hamartoma syndrome with lung involvement. To explore the potential interaction between TSC1 and KRAS activation in lung cancer, mice in which Tsc1 loss and Kras(G12D) expression occur in a small fraction of lung epithelial cells were generated. Mice with a combined Tsc1-Kras(G12D) mutation had dramatically reduced tumor latency (median survival: 11.6-15.6 weeks) in comparison with Kras(G12D) alone mutant mice (median survival: 27.5 weeks). Tsc1-Kras(G12D) tumors showed consistent activation of mTOR (mammalian target of rapamycin)C1 and responded to treatment with rapamycin, leading to significantly improved survival, whereas rapamycin had minor effects on cancers in Kras(G12D) alone mice. Loss of heterozygosity for TSC1 or TSC2 was found in 22% of 86 human lung cancer specimens. However, none of the 80 lung cancer lines studied showed evidence of the lack of expression of either TSC1 or TSC2 or a signaling pattern corresponding to complete loss. These data indicate that Tsc1 loss synergizes with the Kras mutation to enhance lung tumorigenesis in the mouse, but that this is a rare event in human lung cancer. Rapamycin may have unique benefit for patients with lung cancer, for whom the TSC1/TSC2 function is limited.


Asunto(s)
Neoplasias Pulmonares/prevención & control , Proteínas Proto-Oncogénicas p21(ras)/genética , Sirolimus/farmacología , Proteínas Supresoras de Tumor/genética , Animales , Antibióticos Antineoplásicos/farmacología , Apoptosis , Bronquios/efectos de los fármacos , Bronquios/metabolismo , Bronquios/patología , Línea Celular , Activación Enzimática , Humanos , Immunoblotting , Etiquetado Corte-Fin in Situ , Estimación de Kaplan-Meier , Pérdida de Heterocigocidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Noqueados , Complejos Multiproteicos , Mutación , Proteínas , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Serina-Treonina Quinasas TOR , Factores de Transcripción/metabolismo , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/metabolismo
9.
Proc Natl Acad Sci U S A ; 106(12): 4834-9, 2009 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-19261849

RESUMEN

Although 75% of endometrial cancers are treated at an early stage, 15% to 20% of these recur. We performed an integrated analysis of genome-wide expression and copy-number data for primary endometrial carcinomas with extensive clinical and histopathological data to detect features predictive of recurrent disease. Unsupervised analysis of the expression data distinguished 2 major clusters with strikingly different phenotypes, including significant differences in disease-free survival. To identify possible mechanisms for these differences, we performed a global genomic survey of amplifications, deletions, and loss of heterozygosity, which identified 11 significantly amplified and 13 significantly deleted regions. Amplifications of 3q26.32 harboring the oncogene PIK3CA were associated with poor prognosis and segregated with the aggressive transcriptional cluster. Moreover, samples with PIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase (PI3K), a signature that was shared by aggressive tumors without PIK3CA amplification. Tumors with loss of PTEN expression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3K activation signature, high protein expression of the PI3K pathway member STMN1, and an aggressive phenotype in test and validation datasets. However, mutations of PTEN or PIK3CA were not associated with the same expression profile or aggressive phenotype. STMN1 expression had independent prognostic value. The results affirm the utility of systematic characterization of the cancer genome in clinically annotated specimens and suggest the particular importance of the PI3K pathway in patients who have aggressive endometrial cancer.


Asunto(s)
Neoplasias Endometriales/enzimología , Neoplasias Endometriales/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genoma Humano/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Biomarcadores de Tumor/metabolismo , Fosfatidilinositol 3-Quinasa Clase I , Análisis por Conglomerados , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/patología , Activación Enzimática , Femenino , Dosificación de Gen , Humanos , Pérdida de Heterocigocidad/genética , Pronóstico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Estatmina/metabolismo , Análisis de Supervivencia , Proteínas ras/metabolismo
10.
J Pathol ; 217(1): 65-72, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18932182

RESUMEN

Acquired chromosomal aberrations play an important role in tumour development and progression. Such genetic alterations occur in a significant proportion of non-small cell lung carcinomas (NSCLCs) and include amplification of 14q13.3, which contains the TTF1 gene. We asked whether TTF1 amplification is associated with increased TTF1 protein expression in NSCLCs, and whether TTF1 is associated with clinicopathological features, including patient survival. We used a FISH assay and quantitative immunohistochemical staining to interrogate a population-based cohort of 538 NSCLCs from Swiss patients for TTF1 amplification and protein expression. We found TTF1 amplification in approximately 13% of adenocarcinomas (ACs) and in approximately 9% of squamous cell carcinomas (SCCs) and TTF1 amplification was associated with increased TTF1 protein expression. High-level TTF1 expression was significantly associated with smaller tumour size, female gender and longer overall survival only among ACs (median survival 82 versus 28 months; p = 0.002). On multivariate analysis, high TTF1 expression was an independent predictor of favourable prognosis in patients with AC [hazard ratio, 0.56 (95% CI 0.38-0.83); p = 0.008]. We conclude that TTF1 amplification is a mechanism of high-level TTF1 expression in a subset of NSCLCs. When expressed at high levels, this routinely used diagnostic marker is also an independent biomarker of favourable prognosis in AC.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteínas de Unión al ADN/metabolismo , Neoplasias Pulmonares/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Proteínas de Unión al ADN/genética , Femenino , Amplificación de Genes , Humanos , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Factores de Transcripción
11.
Br J Cancer ; 99(2): 245-52, 2008 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-18594528

RESUMEN

Somatic mutations of LKB1 tumour suppressor gene have been detected in human cancers including non-small cell lung cancer (NSCLC). The relationship between LKB1 mutations and clinicopathological characteristics and other common oncogene mutations in NSCLC is inadequately described. In this study we evaluated tumour specimens from 310 patients with NSCLC including those with adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma histologies. Tumours were obtained from patients of US (n=143) and Korean (n=167) origin and screened for LKB1, KRAS, BRAF, and EGFR mutations using RT-PCR-based SURVEYOR-WAVE method followed by Sanger sequencing. We detected mutations in the LKB1 gene in 34 tumours (11%). LKB1 mutation frequency was higher in NSCLC tumours of US origin (17%) compared with 5% in NSCLCs of Korean origin (P=0.001). They tended to occur more commonly in adenocarcinomas (13%) than in squamous cell carcinomas (5%) (P=0.066). LKB1 mutations associated with smoking history (P=0.007) and KRAS mutations (P=0.042) were almost mutually exclusive with EGFR mutations (P=0.002). The outcome of stages I and II NSCLC patients treated with surgery alone did not significantly differ based on LKB1 mutation status. Our study provides clinical and molecular characteristics of NSCLC, which harbour LKB1 mutations.


Asunto(s)
Pueblo Asiatico/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Genes Supresores de Tumor , Neoplasias Pulmonares/genética , Mutación , Proteínas Serina-Treonina Quinasas/genética , Población Blanca/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/etnología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Receptores ErbB/genética , Genes ras , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/etnología , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas B-raf/genética
12.
Oncogene ; 27(34): 4702-11, 2008 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-18408761

RESUMEN

Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to first-generation EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Afatinib , Animales , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Ratones Transgénicos , Células 3T3 NIH , Fosforilación/efectos de los fármacos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Resultado del Tratamiento , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Oncogene ; 26(34): 5023-7, 2007 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-17311002

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/enzimología
14.
Artículo en Inglés | MEDLINE | ID: mdl-16869735

RESUMEN

Genome-era advances in the field of oncology endorse the notion that many tumors may prove vulnerable to targeted therapeutic avenues once their salient molecular alterations are elucidated. Accomplishing this requires both detailed genomic characterization and the ability to identify in situ the critical dependencies operant within individual tumors. To this end, DNA microarray platforms such as high-density single-nucleotide polymorphism (SNP) arrays enable large-scale cancer genome characterization, including copy number and loss-of-heterozygosity analyses at high resolution. Clustering analyses of SNP array data from a large collection of tumor samples and cell lines suggest that certain copy number alterations correlate strongly with the tissue of origin. Such lineage-restricted alterations may harbor novel cancer genes directing genesis or progression of tumors from distinct tissue types. We have explored this notion through combined analysis of genome-scale data sets from the NCI60 cancer cell line collection. Here, several melanoma cell lines clustered on the basis of increased dosage at a region of chromosome 3p containing the master melanocyte regulator MITF. Combined analysis of gene expression data and additional functional studies established MITF as an amplified oncogene in melanoma. MITF may therefore represent a nodal point within a critical lineage survival pathway operant in a subset of melanomas. These findings suggest that, like oncogene addiction, "lineage addiction" may represent a fundamental tumor survival mechanism with important therapeutic implications.


Asunto(s)
Genómica/métodos , Neoplasias/genética , Cromosomas Humanos Par 3/genética , Análisis por Conglomerados , ADN de Neoplasias/genética , Amplificación de Genes , Dosificación de Gen , Perfilación de la Expresión Génica , Genómica/estadística & datos numéricos , Humanos , Hibridación Fluorescente in Situ , Melanoma/genética , Factor de Transcripción Asociado a Microftalmía/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Oncogenes , Polimorfismo de Nucleótido Simple
15.
Artículo en Inglés | MEDLINE | ID: mdl-16869740

RESUMEN

The complete sequencing of the human genome and the development of molecularly targeted cancer therapy have promoted efforts to identify systematically the genetic alterations in human cancer. By high-throughput sequencing of tyrosine kinase genes in human non-small-cell lung cancer, we identified somatic mutations in the kinase domain of the epidermal growth factor receptor tyrosine kinase gene (EGFR) that are correlated with clinical response to EGFR tyrosine kinase inhibitors (TKIs). We have shown that these mutant forms of EGFR induce oncogenic transformation in different cellular systems. Cells whose growth depends on EGFR with mutations in exons 19 and 21 are sensitive to EGFR-TKIs, whereas cells expressing insertion mutations in exon 20 or the T790M point mutant, found in tumor biopsies from patients that relapsed after an initial response to EGFR-TKIs, are resistant. Furthermore, by applying a novel, massively parallel sequencing technology, we have shown that clinically relevant oncogene mutations can be detected in clinical specimens with very low tumor content, thereby enabling optimal patient selection for mutation-directed therapy. In summary, by applying high-throughput genomic resequencing, we have identified a novel therapeutic target, mutant EGFR, in lung cancer and evaluated its role in predicting response to targeted therapy.


Asunto(s)
Adenocarcinoma/genética , Genes erbB-1 , Neoplasias Pulmonares/genética , Mutación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/enzimología , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Receptores ErbB/química , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Ratones , Células 3T3 NIH , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína
16.
Int J Radiat Oncol Biol Phys ; 58(3): 698-704, 2004 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-14967423

RESUMEN

PURPOSE: To evaluate efficacy and toxicity of the Duke University chemoirradiation regimen for locally advanced head-and-neck cancer in a regional community cancer center. METHODS AND MATERIALS: Between June 1998 and June 2002, 50 patients with Stage III or IVA squamous cell carcinoma of the head and neck were treated definitively with concurrent combined modality therapy (CMT). Patients received accelerated, hyperfractionated radiotherapy (AFRT), 1.2-1.25 Gy b.i.d., to a median prescribed dose of 70 Gy. Chemotherapy consisted of cisplatin 12 mg and fluorouracil 600 mg/m(2) daily for 5 consecutive days during Weeks 1 and 6, followed by two cycles after AFRT. Patients with N2-N3 neck disease (n = 21; 42%) were considered for neck dissection depending on their response to AFRT and chemotherapy. Twenty-nine patients with Stage III and IVA disease treated between 1991 and 1997 with definitive RT alone served as historical controls. RESULTS: Forty-nine patients (98%) in the CMT group completed the prescribed AFRT and 38 (76%) completed four cycles of chemotherapy. Three of 8 patients who underwent neck dissection had a pathologically complete response. The median follow-up for all patients was 23 months. The actuarial progression-free survival rate at 2 years was 75% for the CMT group vs. 40% (p <0.01) for the RT group. The overall survival rate was 80% and 43% (p <0.01), respectively, for the CMT and RT groups. Acute Radiation Therapy Oncology Group Grade 3 toxicities for the CMT group were mucosal (n = 50; 100%), skin (n = 9; 18%), and hematologic (n = 3; 6%). Late Grade 3-4 toxicities consisted of pharyngeal stricture (n = 7; 14%), laryngeal chondritis (n = 3; 6%), osteoradionecrosis (n = 2; 4%), and peripheral neuropathy (n = 1; 2%). CONCLUSION: This aggressive regimen of AFRT with concurrent cisplatin and fluorouracil with or without neck dissection is feasible in the community setting for patients with Stage III and IVA head-and-neck cancer. Early results indicated excellent survival, albeit with universal acute mucosal, and considerable, although acceptable, late toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Terapia Combinada , Fraccionamiento de la Dosis de Radiación , Femenino , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias
17.
Proc Natl Acad Sci U S A ; 98(24): 13790-5, 2001 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-11707567

RESUMEN

We have generated a molecular taxonomy of lung carcinoma, the leading cause of cancer death in the United States and worldwide. Using oligonucleotide microarrays, we analyzed mRNA expression levels corresponding to 12,600 transcript sequences in 186 lung tumor samples, including 139 adenocarcinomas resected from the lung. Hierarchical and probabilistic clustering of expression data defined distinct subclasses of lung adenocarcinoma. Among these were tumors with high relative expression of neuroendocrine genes and of type II pneumocyte genes, respectively. Retrospective analysis revealed a less favorable outcome for the adenocarcinomas with neuroendocrine gene expression. The diagnostic potential of expression profiling is emphasized by its ability to discriminate primary lung adenocarcinomas from metastases of extra-pulmonary origin. These results suggest that integration of expression profile data with clinical parameters could aid in diagnosis of lung cancer patients.


Asunto(s)
Adenocarcinoma/clasificación , Expresión Génica , Neoplasias Pulmonares/clasificación , ARN Mensajero , ARN Neoplásico , Adenocarcinoma/genética , Adenocarcinoma/patología , Carcinoma de Células Pequeñas/clasificación , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Escamosas/clasificación , Carcinoma de Células Escamosas/genética , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Metástasis de la Neoplasia , ARN Mensajero/análisis , ARN Neoplásico/análisis , Estudios Retrospectivos , Fumar/efectos adversos , Tasa de Supervivencia , Factores de Tiempo
18.
Cleft Palate Craniofac J ; 38(3): 231-5, 2001 May.
Artículo en Inglés | MEDLINE | ID: mdl-11386430

RESUMEN

OBJECTIVE: This study asked selected mature individuals with Moebius syndrome to discuss the sources of strength and resiliency that allowed them to achieve professional and personal success. DESIGN: Adults with Moebius syndrome were selected in a nonrandom manner based primarily on their affiliation with the Moebius Syndrome Foundation. Following a letter from the author describing the objective, the subjects were interviewed by telephone and were encouraged to respond at length. PARTICIPANTS: Eighteen adults (aged 29 to 70 years) responded. All were or had been gainfully employed in a variety of professional or vocational positions. RESULTS: The respondents reported the following as major sources of resiliency and success: family support, faith, humor, sense of self, special skills, determination, and networking. CONCLUSIONS: The recognition and reinforcement of strengths and resiliences in younger patients may help maximize their professional and personal success as adults.


Asunto(s)
Síndrome de Mobius/psicología , Adaptación Psicológica , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Satisfacción Personal , Calidad de Vida , Apoyo Social
19.
Ann Med ; 33(2): 123-9, 2001 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11327115

RESUMEN

The maintenance of specialized nucleoprotein structures termed telomeres is essential for chromosome stability. Without new synthesis of telomeres at chromosome ends the chromosomes shorten with progressive cell division, eventually triggering either replicative senescence or apoptosis when telomere length becomes critically short. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers. While the mechanisms for telomerase activation in cancers have not been fully defined, they include telomerase catalytic subunit gene (hTERT) amplification and trans-activation of the hTERT promoter by the myc oncogene product. Ectopic expression of hTERT is sufficient to restore telomerase activity in cells that lack the enzyme and can immortalize many cell types. Understanding telomerase biology will eventually lead to several clinically relevant telomerase-based therapies. These applications include inhibiting or targeting telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications.


Asunto(s)
Senescencia Celular/fisiología , Neoplasias/fisiopatología , Telomerasa/fisiología , Telómero/fisiología , Dominio Catalítico/fisiología , Senescencia Celular/genética , Proteínas de Unión al ADN , Genes myc/genética , Genes myc/fisiología , Humanos , Neoplasias/genética , Telomerasa/genética , Telomerasa/metabolismo , Telómero/genética , Transcripción Genética
20.
Nat Biotechnol ; 18(9): 1001-5, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10973224

RESUMEN

Human cancers arise by a combination of discrete mutations and chromosomal alterations. Loss of heterozygosity (LOH) of chromosomal regions bearing mutated tumor suppressor genes is a key event in the evolution of epithelial and mesenchymal tumors. Global patterns of LOH can be understood through allelotyping of tumors with polymorphic genetic markers. Simple sequence length polymorphisms (SSLPs, or microsatellites) are reliable genetic markers for studying LOH, but only a modest number of SSLPs are used in LOH studies because the genotyping procedure is rather tedious. Here, we report the use of a highly parallel approach to genotype large numbers of single-nucleotide polymorphisms (SNPs) for LOH, in which samples are genotyped for nearly 1,500 loci by performing 24 polymerase chain reactions (PCR), pooling the resulting amplification products and hybridizing the mixture to a high-density oligonucleotide array. We characterize the results of LOH analyses on human small-cell lung cancer (SCLC) and control DNA samples by hybridization. We show that the patterns of LOH are consistent with those obtained by analysis with both SSLPs and comparative genomic hybridization (CGH), whereas amplifications rarely are detected by the SNP array. The results validate the use of SNP array hybridization for tumor studies.


Asunto(s)
Carcinoma de Células Pequeñas/genética , Pérdida de Heterocigocidad , Neoplasias Pulmonares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Polimorfismo Genético , Análisis de Secuencia de ADN/métodos , Alelos , Cromosomas Humanos Par 20 , Cromosomas Humanos Par 3 , Genotipo , Heterocigoto , Humanos , Hibridación de Ácido Nucleico/métodos , Ploidias , Polimorfismo de Nucleótido Simple
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