Abstract:
:KRAS mutant tumors are largely recalcitrant to targeted therapies. Genetically engineered mouse models (GEMMs) of Kras mutant cancer recapitulate critical aspects of this disease and are widely used for preclinical validation of targets and therapies. Through comprehensive profiling of exomes and matched transcriptomes of >200 KrasG12D-initiated GEMM tumors from one lung and two pancreatic cancer models, we discover that significant intratumoral and intertumoral genomic heterogeneity evolves during tumorigenesis. Known oncogenes and tumor suppressor genes, beyond those engineered, are mutated, amplified, and deleted. Unlike human tumors, the GEMM genomic landscapes are dominated by copy number alterations, while protein-altering mutations are rare. However, interspecies comparative analyses of the genomic landscapes demonstrate fidelity between genes altered in KRAS mutant human and murine tumors. Genes that are spontaneously altered during murine tumorigenesis are also among the most prevalent found in human indications. Using targeted therapies, we also demonstrate that this inherent tumor heterogeneity can be exploited preclinically to discover cancer-specific and genotype-specific therapeutic vulnerabilities. Focusing on Kras allelic imbalance, a feature shared by all three models, we discover that MAPK pathway inhibition impinges uniquely on this event, indicating distinct susceptibility and fitness advantage of Kras-mutant cells. These data reveal previously unknown genomic diversity among KrasG12D-initiated GEMM tumors, places them in context of human patients, and demonstrates how to exploit this inherent tumor heterogeneity to discover therapeutic vulnerabilities.
journal_name
Proc Natl Acad Sci U S Aauthors
Chung WJ,Daemen A,Cheng JH,Long JE,Cooper JE,Wang BE,Tran C,Singh M,Gnad F,Modrusan Z,Foreman O,Junttila MRdoi
10.1073/pnas.1708391114subject
Has Abstractpub_date
2017-12-19 00:00:00pages
E10947-E10955issue
51eissn
0027-8424issn
1091-6490pii
1708391114journal_volume
114pub_type
杂志文章abstract::In recent years, the field of psychology has begun to conduct replication tests on a large scale. Here, we show that "replicator degrees of freedom" make it far too easy to obtain and publish false-negative replication results, even while appearing to adhere to strict methodological standards. Specifically, using data...
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.1910951116
更新日期:2019-12-17 00:00:00
abstract::The ribosome is one of the major targets for therapeutic antibiotics; however, the rise in multidrug resistance is a growing threat to the utility of our current arsenal. The orthosomycin antibiotics evernimicin (EVN) and avilamycin (AVI) target the ribosome and do not display cross-resistance with any other classes o...
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.1604790113
更新日期:2016-07-05 00:00:00
abstract::Five DNA fragments have been cloned from yeast, chicken, and mouse DNA that titrate lac repressor in an Escherichia coli lac+ I+Z+ wild-type strain when on a multi-copy plasmid. The five repressor-binding sequences have been identified by DNA sequence determinations and DNase cleavage-inhibition patterns. They share t...
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.81.6.1624
更新日期:1984-03-01 00:00:00
abstract::Complete sequences for the intergenic regions of the genome of human respiratory syncytial virus were obtained by dideoxynucleotide sequencing using synthetic oligonucleotides. These experiments established that the 10 respiratory syncytial viral genes are arranged, without additional intervening genes, in the order 3...
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.83.13.4594
更新日期:1986-07-01 00:00:00
abstract::L203 and L227 are mouse monoclonal antibodies specific for human HLA-DR antigens. Their reactivity with multiple, structurally different, HLA-DR antigens was examined by using radioiodinated human lymphoblastoid cells and cell lines, heterozygous or homozygous at the HLA-D locus. Antibody L203 precipitates DR antigens...
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.79.8.2658
更新日期:1982-04-01 00:00:00
abstract::Because the insolubility of the scrapie prion protein (PrP(Sc)) has frustrated structural studies by x-ray crystallography or NMR spectroscopy, we used electron crystallography to characterize the structure of two infectious variants of the prion protein. Isomorphous two-dimensional crystals of the N-terminally trunca...
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.052703499
更新日期:2002-03-19 00:00:00
abstract::In most human follicular B cell lymphomas the bcl-2 gene is up-regulated as a result of the t(14;18) chromosomal translocation generating a hybrid bcl-2-IgH mRNA. Recently, we have identified in t(14;18)-positive cells a bcl-2-IgH mRNA in the antisense orientation, putatively responsible for the overexpression of bcl-...
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.94.15.8150
更新日期:1997-07-22 00:00:00
abstract::Total heterogeneous nuclear RNA from HeLa cells infected with adenovirus for 18-20 hr stimulates amino acid incorporation into protein in a cell-free system from Ehrlich ascites tumors. This stimulation of protein synthesis by the nuclear RNA requires intact nuclei. The role of nuclei in this system is unknown, but 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.71.8.3129
更新日期:1974-08-01 00:00:00
abstract::Spermatogonial stem cells (SSCs) undergo self-renewal divisions to support spermatogenesis throughout life. Although several positive regulators of SSC self-renewal have been discovered, little is known about the negative regulators. Here, we report that F-box and WD-40 domain protein 7 (FBXW7), a component of the Skp...
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.1401837111
更新日期:2014-06-17 00:00:00
abstract::The forebrain cholinergic system promotes higher brain function in part by signaling through the M(1) muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M(1) receptors could improve cognitive function in these patients whil...
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.0900903106
更新日期:2009-09-15 00:00:00
abstract::Jasmonoyl-isoleucine (JA-Ile), the active form of the plant hormone jasmonate (JA), is sensed by the F-box protein CORONATINE INSENSITIVE 1 (COI1), a component of a functional Skp-Cullin-F-box E3 ubiquitin ligase complex. Sensing of JA-Ile by COI1 rapidly triggers genome-wide transcriptional changes that are largely r...
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.1710885114
更新日期:2017-10-17 00:00:00
abstract::Genes that are up- and down-regulated by thyroid hormone in the tail resorption program of Xenopus laevis have been isolated by a gene expression screen, sequenced, and identified in the GenBank data base. The entire program is estimated to consist of fewer than 35 up-regulated and fewer than 10 down-regulated genes; ...
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.93.5.1924
更新日期:1996-03-05 00:00:00
abstract::A full-length cDNA for tryptophan hydroxylase was cloned from rabbit pineal body by screening an expression library with antibody against rat phenylalanine hydroxylase, which crossreacts with rabbit tryptophan hydroxylase. Clones producing immunoreactive material contain sequences homologous to, yet distinct from, phe...
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.84.16.5530
更新日期:1987-08-01 00:00:00
abstract::Hybrid dysgenesis in Drosophila is a syndrome of gonadal atrophy, sterility, and male recombination, and it occurs in the progeny of crosses between males that harbor certain transposable elements (TEs) and females that lack them. Known examples of hybrid dysgenesis in Drosophila melanogaster result from mobilization ...
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.0508192102
更新日期:2005-11-01 00:00:00
abstract::The pathogenesis of tuberculous meningitis, a devastating complication of tuberculosis in man, is poorly understood. We previously reported that rabbits with experimental tuberculous meningitis were protected from death by a combination of antibiotics and thalidomide therapy. Survival was associated with inhibition of...
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.96.10.5657
更新日期:1999-05-11 00:00:00
abstract::The effect of carlorie intake on the development of spontaneous mammary tumors in virgin C3H mice was studied. Only about 10% of the mice fed a low-calorie diet [10 kcal/day (1 kcal = 4.184 kJ)] since weaning developed mammary tumors, compared to about 60% of those mice that were reared on high-calorie diets (16 kcal/...
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.79.24.7758
更新日期:1982-12-01 00:00:00
abstract::The complexed (ribosome-bearing) membrane fraction of Bacillus subtilis contains several proteins (CM-proteins) that are virtually absent from the ribosome-free fraction and hence might be components of the apparatus of protein secretion. We have determined, by trypsin digestion and by labeling with a nonpenetrating r...
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.80.11.3287
更新日期:1983-06-01 00:00:00
abstract::Starting with assignments of proton nuclear magnetic resonance previously made for oxytocin in deuterated dimethylsulfoxide at 220 MHz, we have assigned resonances for the mammalian antidiuretic hormone, lysine vasopressin. The results demonstrate that spectral assignments of neurohypophyseal hormones and their congen...
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.69.7.1920
更新日期:1972-07-01 00:00:00
abstract::For the emergence of early life, the formation of biopolymers such as RNA is essential. However, the addition of nucleotide monomers to existing oligonucleotides requires millimolar concentrations. Even in such optimistic settings, no polymerization of RNA longer than about 20 bases could be demonstrated. How then cou...
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.1303222110
更新日期:2013-05-14 00:00:00
abstract::mRNA-dependent cell-free protein synthesis systems were prepared from a heme-deficient ole3 mutant of the yeast Saccharomyces cerevisiae grown either in the absence or in the presence of the heme precursor delta-aminolevulinate. When supplemented with total yeast mRNA, the two systems-from heme-deficient and from heme...
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.79.24.7609
更新日期:1982-12-01 00:00:00
abstract::A fraction obtained by gel filtration at neutral pH of the extracellular Hb of Lumbricus terrestris dissociated either at pH 9.8 or at pH 4.0, consisting of the three subunits D1 (31 kDa), D2 (37 kDa), and T (50 kDa), was found to produce two peaks when subjected to gel filtration on Superose 6 at pH 7. The first peak...
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.84.21.7532
更新日期:1987-11-01 00:00:00
abstract::Human C5a, a complement-derived anaphylatoxin, is a potent mediator of human leukocyte chemotaxis. Using a homogeneous preparation of C5a that was 125I-labeled, we have demonstrated the presence of a specific cellular receptor for this glycoprotein on intact human polymorphonuclear leukocytes. Cellular uptake of the r...
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.75.8.3943
更新日期:1978-08-01 00:00:00
abstract::Noninvasive prenatal testing using fetal DNA in maternal plasma is an actively researched area. The current generation of tests using massively parallel sequencing is based on counting plasma DNA sequences originating from different genomic regions. In this study, we explored a different approach that is based on the ...
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.1406103111
更新日期:2014-06-10 00:00:00
abstract::We described previously a mutation in maize, hcf106, caused by the insertion of a Mu1 transposon. When the Mu transposon system is in an active phase, hcf106 conditions a nonphotosynthetic, pale green phenotype. However, when the Mu system is inactive (a state correlated with hypermethylation of Mu elements), the plan...
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.88.8.3502
更新日期:1991-04-15 00:00:00
abstract::August-Copenhagen-Irish (ACI) rats are unique in that the ovary-intact females develop high incidence of mammary cancers induced solely by hormones upon prolonged exposure to high levels of estrogen alone. Studies have also shown that such prolonged exposure to high-dose estrogen results in human-like aneuploid mammar...
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.0710535105
更新日期:2008-03-04 00:00:00
abstract::Aged rats, displaying impairments in spatial learning and memory associated with marked cellular atrophy of forebrain cholinergic neurons, received intracerebroventricular infusions of one of the four neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), or neurotrop...
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.91.18.8607
更新日期:1994-08-30 00:00:00
abstract::Rabbit chondrocyte cultures on plastic dishes are capable of depositing a cartilaginous matrix, although the matrix does not calcify unless high levels of phosphate are added to the medium. In the present study, we cultivated a pelleted mass of rabbit growth-plate chondrocytes in the presence of Eagle's minimum essent...
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.85.24.9552
更新日期:1988-12-01 00:00:00
abstract::Two functional human dUTP pyrophosphatase (dUTPase; EC 3.6.1.23) cDNAs were isolated from a cDNA expression library by genetic complementation in Escherichia coli. These cDNAs differed in size but exhibited a common overlapping DNA sequence. Contained within this sequence was a single long open reading frame sufficien...
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.89.17.8020
更新日期:1992-09-01 00:00:00
abstract::Over the last decade a variety of MS measurements, such as HD exchange, collision cross sections, and electron capture dissociation (ECD), have been used to characterize protein folding in the gas phase, in the absence of solvent. To the extensive data already available on ubiquitin, here photofragmentation of its ECD...
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.212643599
更新日期:2002-12-10 00:00:00
abstract::The conversion of cells from a normal phenotype to full malignancy apparently requires multiple genetic events. Efforts to reconstruct multistep tumorigenesis in cell culture have shown that two types of oncogenes (typified by HRAS and MYC) can cooperate to elicit complete transformation. Transformation of embryonic r...
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.85.12.4355
更新日期:1988-06-01 00:00:00