Abstract:
:Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.
journal_name
Oncogenejournal_title
Oncogeneauthors
Knickelbein K,Tong J,Chen D,Wang YJ,Misale S,Bardelli A,Yu J,Zhang Ldoi
10.1038/s41388-018-0289-xsubject
Has Abstractpub_date
2018-08-01 00:00:00pages
4599-4610issue
33eissn
0950-9232issn
1476-5594pii
10.1038/s41388-018-0289-xjournal_volume
37pub_type
杂志文章相关文献
ONCOGENE文献大全abstract::RNA-binding proteins play key roles in the posttranscriptional regulation of mRNA during cancer progression. Here, we show that RNA-binding motif protein 43 (RBM43) is significantly downregulated in human tumors, and its low expression is correlated with poor prognosis in patients with HCC. Overexpression of RBM43 sup...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-020-1380-7
更新日期:2020-08-01 00:00:00
abstract::The Ets family of transcription factors is one of a growing number of master regulators of development. This family was originally defined by the presence of a conserved DNA binding domain, the Ets domain. To date, nearly 30 members of this family have been identified and implicated in a wide range of physiological an...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1204038
更新日期:2000-12-18 00:00:00
abstract::GATA3 is an essential transcription factor that was first identified as a regulator of immune cell function. In recent microarray analyses of human breast tumors, both normal breast luminal epithelium and estrogen receptor (ESR1)-positive tumors showed high expression of GATA3. We sequenced genomic DNA from 111 breast...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1207966
更新日期:2004-10-07 00:00:00
abstract::Activation of the Met tyrosine kinase growth factor receptor by its ligand HGF/SF has been shown to increase in vitro invasiveness in epithelial cell lines. To study the effect of Met-HGF/SF signaling in breast cancer cells, we transfected met, hgf/sf and dominant negative (DN) forms of met into the poorly differentia...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1203557
更新日期:2000-05-11 00:00:00
abstract::Expression of the c-myc gene is often elevated in human colorectal tumors, but reported amplification of the locus is rare. Here we demonstrate that modest amplification of c-myc is frequently found in aggressive subtypes of colorectal cancer. Careful quantitation of c-myc copy number has shown amplification in 53.8% ...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1991-01-01 00:00:00
abstract::A previous report demonstrated that AP-2alpha favors the survival of ovarian cancer patients by clinical findings. However, the functional roles of AP-2alpha in human ovarian cancers have not been determined. To clarify the roles, we overexpressed AP-2alpha in SKOV3 human ovarian cancer cells, which originally possess...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1207723
更新日期:2004-07-15 00:00:00
abstract::Viruses have been engineered to replicate selectively in cancer cells, based on a number of innovative principles. Several of these viruses have entered clinical trials and have proven relatively safe, and have shown evidence of efficacy. However, further research is required to enable these agents to function systemi...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1209064
更新日期:2005-11-21 00:00:00
abstract::Primary neonatal Balb/c keratinocyte (NEK) cultures grown, using 3T3 feeder cell support in high calcium, serum supplemented medium, were transfected with EJ-Ha-ras or v-fos DNA sequences and pSV2 neo. Several neo resistant clones were isolated and several established cell lines expressing the transfected gene product...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1989-11-01 00:00:00
abstract::Each step in the synthesis of functional transcript by RNA polymerase II provides a level at which gene expression can be regulated. Control over the elongation phase of transcription is a recognized regulatory mechanism in prokaryotes; however, only recently have examples of conditional transcription elongation block...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:
更新日期:1990-06-01 00:00:00
abstract::Advanced Bladder Cancer (BLCA) remains a clinical challenge that lacks effective therapeutic measures. Here, we show that distinct, stage-wise metabolic alterations in BLCA are associated with the loss of function of aldehyde oxidase (AOX1). AOX1 associated metabolites have a high predictive value for advanced BLCA an...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-019-0902-7
更新日期:2020-10-01 00:00:00
abstract::Proliferating cell nuclear antigen (PCNA) plays an essential role in nucleic acid metabolism as a component of the replication and repair machinery. This toroidal-shaped protein encircles DNA and can slide bidirectionally along the duplex. One of the well-established functions for PCNA is its role as the processivity ...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1200886
更新日期:1997-02-13 00:00:00
abstract::The RAD17 gene product of S. Pombe is an essential component of the checkpoint control pathway which responds to both DNA damage and disruption of replication. We have identified a human cDNA that encodes a polypeptide which is structurally conserved with the S. Pombe Rad17 protein. The human gene, designated hRAD17, ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202469
更新日期:1999-03-04 00:00:00
abstract::Approximately 80% of breast cancers express the estrogen receptor-alpha (ERalpha) and are treated with anti-estrogens. Resistance to these agents is a major cause of mortality. We have shown that estrogen inhibits Notch, whereas anti-estrogens or estrogen withdrawal activate Notch signaling. Combined inhibition of Not...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2009.323
更新日期:2010-01-14 00:00:00
abstract::The antifolates were the first class of antimetabolites to enter the clinics more than 50 years ago. Over the following decades, a full understanding of their mechanisms of action and chemotherapeutic potential evolved along with the mechanisms by which cells develop resistance to these drugs. These principals served ...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1206946
更新日期:2003-10-20 00:00:00
abstract::Our previous work with primary bovine fibroblasts demonstrated that quercetin, a potent mutagen found in high levels in bracken fern (Pteridium aquilinum), arrested cells in G1 and G2/M, in correlation with p53 activation. The expression of bovine papillomavirus type 4 (BPV-4) E7 overcame this arrest and lead to the d...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206848
更新日期:2003-08-21 00:00:00
abstract::Replication origins are 'licensed' for a single initiation event by loading Mcm2-7 complexes during late mitosis and G1. Licensing is blocked at other cell cycle stages by the activity of cyclin-dependent kinases and a small protein called geminin. Here, we describe the effects of over-expressing a non-degradable form...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1205910
更新日期:2002-09-26 00:00:00
abstract::Although transforming ras oncogenes have been implicated as causative factors in liver cell transformation, the exact function and phenotypic alterations generated by the expression of such transforming genes in liver epithelial cells has yet to be defined. We have utilized a retroviral vector system to deliver an ind...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1988-09-01 00:00:00
abstract::Synemin (SYNM) is a type IV intermediate filament that has recently been shown to interact with the LIM domain protein zyxin, thereby possibly modulating cell adhesion and cell motility. Owing to this multiplicity of potential functions relevant to cancer development, we initiated a study to decipher SYNM expression a...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2010.229
更新日期:2010-08-26 00:00:00
abstract::Treatment of many cancers relies on the combined action of several genotoxins, but the detrimental effect of these drugs on normal cells can cause severe side effects. One major challenge in anticancer therapy is therefore to increase the selectivity of current treatments toward cancer cells in order to spare normal c...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1207999
更新日期:2004-11-25 00:00:00
abstract::In addition to breast and ovarian cancer in women, recent evidence suggests that germ-line mutations of the breast cancer susceptibility gene-1 (BRCA1) also confer an increased life-time risk for prostate cancer in male probands. However, it is not known if and how BRCA1 functions in prostate cancer. We stably express...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202116
更新日期:1998-06-11 00:00:00
abstract::While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not found in astrocytomas. We have previously demonstrated that the activation of receptor tyrosine kinases expressed by malignant human astrocytoma cells and specimens results in functional upregulation of the Ras signalling pathway and inc...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1203105
更新日期:1999-12-09 00:00:00
abstract::The human papillomavirus (HPV) E6 protein is one of three oncoproteins encoded by the virus. It has long been recognized as a potent oncogene and is intimately associated with the events that result in the malignant conversion of virally infected cells. In order to understand the mechanisms by which E6 contributes to ...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1204869
更新日期:2001-11-26 00:00:00
abstract::The RAF-mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated kinase 1/2 (RAF-MEK1/2-ERK1/2) pathway is activated in many human tumours and can protect cells against growth factor deprivation; however, most such studies have relied upon overexpression of RAF or MEK constructs that are not found in...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2008.335
更新日期:2008-12-04 00:00:00
abstract::Among surface molecules expressed on endothelial cells, endoglin (CD105) is emerging as a prime vascular target for antiangiogenetic cancer therapy. CD105 is a cell membrane glycoprotein mainly expressed on endothelial cells and overexpressed on tumor-associated vascular endothelium, which functions as an accessory co...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1206813
更新日期:2003-09-29 00:00:00
abstract::The LoVo colon carcinoma cell line that presents two wild type p53 alleles was used as the recipient for a series of transfections with p53 expression vectors coding for wild-type or three different mutants (143ala, 175his or 273his). The parental cell line as well as all clones that had rearranged the plasmid with co...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1996-02-15 00:00:00
abstract::Non-small cell lung carcinomas (NSCLCs) are typically resistant against apoptosis induced by standard chemotherapy. We evaluated the effects of the two potential antitumor agents of the lamellarin class on a highly apoptosis-resistant NSCLC cell line. Both the marine alkaloid lamellarin-D and its synthetic amino deriv...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1210833
更新日期:2008-03-27 00:00:00
abstract::Beta-transducin repeats-containing proteins (beta-TrCP) serve as the substrate recognition subunits for the SCFbeta-TrCP E3 ubiquitin ligases. These ligases ubiquitinate specifically phosphorylated substrates and play a pivotal role in the regulation of cell division and various signal transduction pathways, which, in...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1207389
更新日期:2004-03-15 00:00:00
abstract::Aberrant activation of anaplastic lymphoma kinase (ALK) can cause sporadic and familial neuroblastoma. Using a proteomics approach, we identified Bruton's tyrosine kinase (BTK) as a novel ALK interaction partner, and the physical interaction was confirmed by co-immunoprecipitation. BTK is expressed in neuroblastoma ce...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-018-0397-7
更新日期:2018-11-01 00:00:00
abstract::We analysed 31 non-glioblastoma astrocytomas for alterations in p53 protein expression and for mutations in the p53 gene. Immunohistochemistry detected p53 protein accumulation in 71% (five of seven) of juvenile pilocytic astrocytomas (WHO grade I), 63% (five of eight) of astrocytomas (WHO grade II), and 63% (10 of 16...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1994-03-01 00:00:00
abstract::The v-myb oncogene of the avian myeloblastosis virus (AMV) is unique among known oncogenes in that it causes only acute leukemia in animals and transforms only hematopoietic cells in culture. AMV was discovered in the 1930s as a virus that caused a disease in chickens that is similar to acute myelogenous leukemia in h...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1202745
更新日期:1999-05-13 00:00:00