Abstract:
:We describe a molecular resistance biomarker to gefitinib, epithelial membrane protein-1 (EMP-1). Gefitinib is a small-molecule inhibitor that competes for the ATP-binding site on EGF receptor (EGFR) and has been approved for patients with advanced lung cancers. Treatment with gefitinib has resulted in clinical benefit in patients, and, recently, heterozygous somatic mutations within the EGFR catalytic domain have been identified as a clinical correlate to objective response to gefitinib. However, clinical resistance to gefitinib limits the utility of this therapeutic to a fraction of patients, and objective clinical responses are rare. We aimed to assess the molecular phenotype and mechanism of in vivo gefitinib resistance in xenograft models and in patient samples. We generated in vivo gefitinib-resistance models in an adenocarcinoma xenograft model by serially passaging tumors in nude mice in presence of gefitinib until resistance was acquired. EMP-1 was identified as a surface biomarker whose expression correlated with acquisition of gefitinib resistance. EMP-1 expression was further correlated with lack of complete or partial response to gefitinib in lung cancer patient samples as well as clinical progression to secondary gefitinib resistance. EMP-1 expression and acquisition of gefitinib clinical resistance was independent of gefitinib-sensitizing EGFR somatic mutations. This report suggests the role of the adhesion molecule, EMP-1, as a biomarker of gefitinib clinical resistance, and further suggests a probable cross-talk between this molecule and the EGFR signaling pathway.
journal_name
Proc Natl Acad Sci U S Aauthors
Jain A,Tindell CA,Laux I,Hunter JB,Curran J,Galkin A,Afar DE,Aronson N,Shak S,Natale RB,Agus DBdoi
10.1073/pnas.0502113102keywords:
subject
Has Abstractpub_date
2005-08-16 00:00:00pages
11858-63issue
33eissn
0027-8424issn
1091-6490pii
0502113102journal_volume
102pub_type
杂志文章abstract::Metallothionein (MT) has several putative roles in metal detoxification, in Zn and Cu homeostasis, in scavenging free radicals, and in the acute phase response. Mice of mixed 129/Ola and C57BL/6J background with targeted disruption of MT-I and MT-II genes are more sensitive to toxic metals and oxidative stress. We not...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.1.358
更新日期:1998-01-06 00:00:00
abstract::Controls of stem cell maintenance and early differentiation are known in several systems. However, the progression from stem cell self-renewal to overt signs of early differentiation is a poorly understood but important problem in stem cell biology. The Caenorhabditis elegans germ line provides a genetically defined m...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0912704107
更新日期:2010-02-02 00:00:00
abstract::The mid-winter development of refractoriness to melatonin (Mel) triggers recrudescence of the atrophied reproductive apparatus of rodents. As a consequence, over-wintering animals become reproductively competent just before the onset of spring conditions favorable for breeding. The neural target tissues that cease to ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.111140398
更新日期:2001-05-22 00:00:00
abstract::Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-c...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0901166106
更新日期:2009-04-14 00:00:00
abstract::Prey shifts in carnivorous predators are events that can initiate the accelerated generation of new biodiversity. However, it is seldom possible to reconstruct how the change in prey preference occurred. Here we describe an evolutionary "smoking gun" that illuminates the transition from worm hunting to fish hunting am...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1424435112
更新日期:2015-04-21 00:00:00
abstract::Experimental work in animals has shown that memory formation depends on a cascade of molecular events. Here we show that variability of human memory performance is related to variability in genes encoding proteins of this signaling cascade, including the NMDA and metabotrobic glutamate receptors, adenylyl cyclase, CAM...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0510212103
更新日期:2006-03-14 00:00:00
abstract::Elucidation of mechanisms that regulate hematopoietic stem cell self-renewal and differentiation would be facilitated by the identification of defined culture conditions that allow these cells to be amplified. We now demonstrate a significant net increase (3-fold, P < 0.001) in vitro of cells that are individually abl...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.94.25.13648
更新日期:1997-12-09 00:00:00
abstract::Paired immunoglobulin-like type 2 receptor α (PILRα) and β (PILRβ) belong to the PILR family and are related to innate immune regulation in various species. Despite their high sequence identity, PILRα and PILRβ are shown to have variant sialic acid (SA) binding avidities. To explore the molecular basis of this interac...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1320716111
更新日期:2014-06-03 00:00:00
abstract::The mutagenic effect of low linear energy transfer ionizing radiation is reduced for a given dose as the dose rate (DR) is reduced to a low level, a phenomenon known as the direct DR effect. Our reanalysis of published data shows that for both somatic and germ-line mutations there is an opposite, inverse DR effect, wi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.090099497
更新日期:2000-05-09 00:00:00
abstract::Mutations in the potassium channel gene KCNQ4 underlie DFNA2, an autosomal dominant form of progressive hearing loss in humans. In the mouse cochlea, the transcript has been found exclusively in the outer hair cells. By using specific antibodies, we now show that KCNQ4 is situated at the basal membrane of these sensor...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.97.8.4333
更新日期:2000-04-11 00:00:00
abstract::Using a water-based prebiotic model of sugar synthesis involving glycolaldehyde self-condensation, we demonstrate that homochiral L-dipeptide catalysts lead to the stereospecific syntheses of tetroses. The asymmetric effect is largest for erythrose, which may reach a D-enantiomeric excess of >80% with L-Val-L-Val cata...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0602320103
更新日期:2006-08-22 00:00:00
abstract::In clinical trials comparing two treatments, one would often like to control the probability of erroneous decision while minimizing not the total sample size but the number of patients given the inferior treatment. To do this obviously requires that one use a datadependent allocation rule for the two treatments rather...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 临床试验,杂志文章
doi:10.1073/pnas.69.10.2993
更新日期:1972-10-01 00:00:00
abstract::A single dose of N-methyl-N-nitrosourea given to sexually immature female Buf/N rats produces a high incidence of mammary adenocarcinomas. A large percentage of these tumors contain the Ha-ras oncogene, activated by a G----A transition at the second nucleotide of codon 12. Copenhagen rats, on the other hand, are compl...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.89.3.1001
更新日期:1992-02-01 00:00:00
abstract::Linkage disequilibrium between polymorphisms in a natural population may result from various evolutionary forces, including random genetic drift due to sampling of gametes during reproduction, restricted migration between subpopulations in a subdivided population, or epistatic selection. In this report, we present evi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.92.20.9047
更新日期:1995-09-26 00:00:00
abstract::Glutamine synthetase (GS) is expressed in the neural retina only in Muller glia cells and is inducible with cortisol. A chicken genomic clone that contains at least part of the coding region for the GS enzyme was used to investigate developmental changes in the level of GS mRNA in embryonic chicken retina. A major GS ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.83.23.9060
更新日期:1986-12-01 00:00:00
abstract::Scientific journal publications, and their contributions to knowledge, can be described by their depth (specialized, domain-specific knowledge extensions) and breadth (topical scope, including spanning multiple knowledge domains). Toward generating hypotheses about how scientists' personal dispositions would uniquely ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1421286112
更新日期:2015-03-24 00:00:00
abstract::Interdigital webbing has evolved repeatedly in tropical salamanders (bolitoglossines). This derived foot morphology is only one of many homoplastic traits in this diverse amphibian clade. Indeed, few if any morphological traits sort lineages within this clade. We investigate the processes underlying the homoplastic ev...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0710216105
更新日期:2007-12-18 00:00:00
abstract::Attention allows animals to respond selectively to competing stimuli, enabling some stimuli to evoke a behavioral response while others are ignored. How the brain does this remains mysterious, although it is increasingly evident that even animals with the smallest brains display this capacity. For example, insects res...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1323297111
更新日期:2014-04-01 00:00:00
abstract::The conformational effects of different amino acid substitutions (lysine, serine, proline, and D-valine) for glycine at position 12 in the p21 oncogene-encoded proteins have been investigated by using conformational energy calculations. The normal cellular gene codes for a glycine at position 12 in the amino acid sequ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.82.11.3596
更新日期:1985-06-01 00:00:00
abstract::Nanometer-scale pores have demonstrated potential for the electrical detection, quantification, and characterization of molecules for biomedical applications and the chemical analysis of polymers. Despite extensive research in the nanopore sensing field, there is a paucity of theoretical models that incorporate the in...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1002194107
更新日期:2010-07-06 00:00:00
abstract::Metalloproteases (MPs) are a large and diverse class of enzymes implicated in numerous physiological and pathological processes, including tissue remodeling, peptide hormone processing, and cancer. MPs are tightly regulated by multiple posttranslational mechanisms in vivo, hindering their functional analysis by conven...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0402784101
更新日期:2004-07-06 00:00:00
abstract::Nicotinic AChRs (nAChRs) represent a paradigm for ligand-gated ion channels. Despite intensive studies over many years, our understanding of the mechanisms of activation and inhibition for nAChRs is still incomplete. Here, we present molecular dynamics (MD) simulations of the alpha7 nAChR ligand-binding domain, both i...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0710530105
更新日期:2008-06-17 00:00:00
abstract::Insertion mutations previously constructed within the proximal region of the yeast invertase signal sequence did not interfere with secretion or glycosylation of the enzyme. We now describe deletion mutations within the same signal sequence. Large deletions truncating the hydrophobic core of the signal peptide prevent...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.83.14.5033
更新日期:1986-07-01 00:00:00
abstract::The light-harvesting chlorophyll a/b protein (LHCP) is an integral thylakoid membrane protein. It is made in the cytosol as a precursor (pLHCP), imported into chloroplasts, and subsequently integrated into thylakoids. Integration of pLHCP into thylakoids requires a stromal protein factor that functions in part to main...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.90.18.8552
更新日期:1993-09-15 00:00:00
abstract::Establishing a timeline for the evolution of novelties is a common, unifying goal at the intersection of evolutionary and developmental biology. Analyses of gene regulatory networks (GRNs) provide the ability to understand the underlying genetic and developmental mechanisms responsible for the origin of morphological ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1610603114
更新日期:2017-06-06 00:00:00
abstract::Emergence of antiestrogen-resistant cells in MCF-7 cells during suppression of estrogen signaling is a widely accepted model of acquired breast cancer resistance to endocrine therapy. To obtain insight into the genomic basis of endocrine therapy resistance, we characterized MCF-7 monoclonal sublines that survived 21-d...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0907560106
更新日期:2009-08-25 00:00:00
abstract::Ribonucleotide reductase (RNR) catalyzes the conversion of nucleoside diphosphates to deoxynucleoside diphosphates (dNDPs). The Escherichia coli class Ia RNR uses a mechanism of radical propagation by which a cysteine in the active site of the RNR large (α2) subunit is transiently oxidized by a stable tyrosyl radical ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1220691110
更新日期:2013-03-05 00:00:00
abstract::The retrosplenial cortex (RSC) is part of a network of interconnected cortical, hippocampal, and thalamic structures harboring spatially modulated neurons. The RSC contains head direction cells and connects to the parahippocampal region and anterior thalamus. Manipulations of the RSC can affect spatial and contextual ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1313222111
更新日期:2014-06-10 00:00:00
abstract::Arabinose-binding protein, maltose-binding protein, and lambda receptor are synthesized in vitro on membrane-bound polysomes from Escherichia coli. All three proteins are exported from the cytoplasm of E. coli and all three are made in vitro in a form a few thousand daltons larger than the authentic protein. The large...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.75.3.1209
更新日期:1978-03-01 00:00:00
abstract::The interaction of interleukin 8 (IL-8) with heparin was studied by using synthetic IL-8 analogs with C- and N-terminal truncations. Elimination of the N-terminal region preceding the first cysteine, which constitutes the IL-8 receptor binding site, did not affect the affinity to heparin-Sepharose. Affinity, however, ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.90.15.7158
更新日期:1993-08-01 00:00:00