Abstract:
:Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-κB activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.
journal_name
Oncogenejournal_title
Oncogeneauthors
Li Y,Bouchlaka MN,Wolff J,Grindle KM,Lu L,Qian S,Zhong X,Pflum N,Jobin P,Kahl BS,Eickhoff JC,Wuerzberger-Davis SM,Miyamoto S,Thomas CJ,Yang DT,Capitini CM,Rui Ldoi
10.1038/onc.2016.155subject
Has Abstractpub_date
2016-12-01 00:00:00pages
6223-6234issue
48eissn
0950-9232issn
1476-5594pii
onc2016155journal_volume
35pub_type
杂志文章相关文献
ONCOGENE文献大全abstract::Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are media...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-018-0563-y
更新日期:2019-03-01 00:00:00
abstract::Invadopodia are cell protrusions that mediate cancer cell extravasation but the microenvironmental cues and signaling factors that induce invadopodia formation during extravasation remain unclear. Using intravital imaging and loss of function experiments, we determined invadopodia contain receptors involved in chemota...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-018-0667-4
更新日期:2019-05-01 00:00:00
abstract::Deregulation of Wnt signalling has recently been implicated in human renal cancer. Here, we directly test this association by using a Cre-LoxP strategy to inactivate the Adenomatous Polyposis Coli (Apc) gene in the murine renal epithelium. Mice homozygous for a conditional Apc allele were intercrossed with mice transg...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208956
更新日期:2005-12-08 00:00:00
abstract::We have expressed wild-type and human tumour-derived mutant p53 cDNA genes in the fission yeast Schizosaccharomyces pombe. In the case of one mutant this resulted in a growth arrest of recipient yeast cells. In contrast, wild-type p53 and three other mutant proteins tested did not block outgrowth of colonies. Human an...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1991-09-01 00:00:00
abstract::Previous studies have shown that the adenovirus E1A oncoprotein can bind to and inactivate the retinoblastoma tumor suppressor protein (pRb) and the transcriptional coactivators CBP/p300. In this study, wild-type E1A12S or two deletion mutants (delN, which binds pRb but not CBP/p300; delCR2, which binds to CBP/p300 bu...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1205050
更新日期:2002-02-07 00:00:00
abstract::bcl-XS, a member of the bcl-2 family, has been shown to induce and/or sensitize some cells to undergo programmed cell death, and to negate the anti-apoptotic activity of bcl-XL and bcl-2 by mechanisms which are still uncertain. To help understand these mechanisms we have established stable derivatives of the K12 rat c...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202224
更新日期:1998-12-10 00:00:00
abstract::From the sequences of Rel/NF-kappa B and I kappa B proteins, we constructed an alignment of their Rel Homology Domain (RHD) and ankyrin repeat domain. Using this alignment, we performed tree reconstruction with both distance matrix and parsimony analysis and estimated the branching robustness using bootstrap resamplin...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201471
更新日期:1997-12-11 00:00:00
abstract::The transcriptional activity of the androgen receptor (AR) is regulated by both ligand binding and post-translational modifications, including acetylation and small ubiquitin-like modifier (SUMO)ylation. Histone deacetylases (HDACs) are known to catalyze the removal of acetyl groups from both histones and non-histone ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2010.600
更新日期:2011-05-12 00:00:00
abstract::The Cdk inhibitor p21(WAF1/CIP1) is a negative regulator of the cell cycle, although its expression is induced by a number of mitogens that promote cell proliferation. We have found that E2F1 and E2F3, transcription factors that activate genes required for cell cycle progression, are strong activators of the p21 promo...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202240
更新日期:1998-12-31 00:00:00
abstract::Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor, which upon activation, recruits downstream proteins by poly(ADP-ribosyl)ation (PARylation). However, it remains largely unclear how PARP1 activity is regulated. Interestingly, the data obtained through this study revealed that PARP1 was co-immunoprecipitate...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-018-0506-7
更新日期:2019-02-01 00:00:00
abstract::Neuroendocrine prostate cancer (NEPC) has increasingly become a clinical challenge. The mechanisms by which neuroendocrine (NE) cells arises from prostate adenocarcinoma cells are poorly understood. FOXA1 is a transcription factor of the forkhead family that is required for prostate epithelial differentiation. In this...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2017.50
更新日期:2017-07-13 00:00:00
abstract::Activating mutations of the ALK receptor occur in a subset of neuroblastoma tumors. We previously demonstrated that Alk mutations cooperate with MYCN overexpression to induce neuroblastoma in mice and identified Ret as being strongly upregulated in MYCN/Alkmut tumors. By a genetic approach in vivo, we now document an ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-017-0039-5
更新日期:2018-03-01 00:00:00
abstract::Arsenite trioxide (As2O3) induces apoptosis in several cell lines by disturbing key signal transduction pathways through its oxidative properties. Here, we report that As2O3 also induces the phosphorylation of the retinoid receptor RXRalpha, subsequent to oxidative damages and the activation of the stress-activated pr...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208402
更新日期:2005-03-31 00:00:00
abstract::Apoptin, a small protein from the chicken anemia virus, has attracted attention because of its specificity in killing tumor cells. Localization of apoptin in the nucleus of tumor cells has been shown to be vital for proapoptotic activity, however, targeted expression of apoptin in the nucleus of normal cells does not ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1210958
更新日期:2008-05-08 00:00:00
abstract::Downregulation of the cellular retinol-binding protein-I (CRBP-I) occurs in breast and other human cancers, but its significance is not well understood. Recently, we showed that restoration of CRBP-I expression in transformed MTSV1-7 breast epithelial cells increased retinoic receptor activity, inhibited anoikis, prom...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208347
更新日期:2005-02-24 00:00:00
abstract::Estrogen receptor alpha gene (ESR1) mutations occur frequently in ER-positive metastatic breast cancer, and confer clinical resistance to aromatase inhibitors. Expression of the ESR1 Y537S mutation induced an epithelial-mesenchymal transition (EMT) with cells exhibiting enhanced migration and invasion potential in vit...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-020-01563-x
更新日期:2020-12-15 00:00:00
abstract::The p53 tumor suppressor protein plays a central role in maintaining genomic integrity by occupying a nodal point in the DNA damage control pathway. Here it integrates a wide variety of signals, responding in one of several ways, that is, cell cycle arrest, senescence or programmed cell death (apoptosis). Mutations in...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1209952
更新日期:2007-03-08 00:00:00
abstract::The p53 oncosuppressor is strictly maintained in an inactive form under normal conditions, while it is post-translationally activated by a variety of stresses, enacting different protective biological functions. Since one critical issue in cancer gene therapy is tumor specificity, we asked whether the tight p53 regula...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1207042
更新日期:2004-01-15 00:00:00
abstract::Transforming growth factor beta1 (TGF-beta1) belongs to a family of polypeptide factors, whose cytostatic and apoptotic functions help restrain the growth of mammalian cells. Although solid data established the role of TGF-beta's as suppressor factors in tumorigenic processes, in the context of an advanced stage of di...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208664
更新日期:2005-06-30 00:00:00
abstract::Soft tissue sarcomas are a heterogeneous group of neoplasms with various histological subtypes. Up to now, no individual causal molecular markers for prognosis and therapeutic success have been identified. A tumorigenic connection between the oncogene product Mdm2 and tumor suppressor p53 is generally accepted, but th...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201646
更新日期:1998-03-05 00:00:00
abstract::The skin represents a physical and chemical barrier against invading pathogens, which is additionally supported by restriction factors that provide intrinsic cellular immunity. These factors detect viruses to block their replication cycle. Here, we uncover the Myb-related transcription factor, partner of profilin (MYP...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-018-0398-6
更新日期:2018-11-01 00:00:00
abstract::p53 is known to play a role in iron homeostasis and is required for FDXR-mediated iron metabolism via iron regulatory protein 2 (IRP2). Interestingly, p53 is frequently mutated in tumors wherein iron is often accumulated, suggesting that mutant p53 may exert its gain of function by altering iron metabolism. In this st...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-019-0876-5
更新日期:2019-08-01 00:00:00
abstract::The NRG4 gene is a member of a family of four genes that encode a class of epidermal growth factors. This gene has been reported to express a protein designated here as NRG4A1. We describe here a novel splice variant of the NRG4 gene, NRG4A2, which encodes a C-terminal region containing a predicted type I PDZ-binding ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1210689
更新日期:2008-01-24 00:00:00
abstract::Cells from patients with the human genetic disorder ataxia-telangiectasia (A-T) are defective in the activation of cell cycle checkpoints in response to ionizing radiation damage. In order to understand the role of ATM in checkpoint control we investigated whether Schizosaccaromyces pombe chk1, a protein kinase implic...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202257
更新日期:1999-01-07 00:00:00
abstract::We recently reported the cloning and sequencing of the mouse A-myb proto-oncogene cDNA and the abundant expression of this mRNA primarily in the testis of adult mice. The A-myb mRNA is detectable by in situ hybridization specifically in the spermatogenic cells, and is downregulated during terminal differentiation. A l...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1996-09-19 00:00:00
abstract::The RAS/RAF mitogen-activated protein kinase pathway (MAPK) is highly active in many tumor types including the majority of high-grade gliomas and expression of activated RAS or RAF in neural progenitor cells combined with either AKT activation or Ink4a/Arf loss leads to the development of high-grade gliomas in vivo. T...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2010.513
更新日期:2011-03-17 00:00:00
abstract::Understanding the molecular mechanisms that underlie the aggressive behavior and relapse of breast cancer may help in the development of novel therapeutic interventions. CUB-domain-containing protein 1 (CDCP1), a transmembrane adaptor protein, is highly maintained and required in the context of cellular metastatic pot...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-018-0372-3
更新日期:2018-10-01 00:00:00
abstract::Low oxygen tension (hypoxia) is a common feature of solid tumors and stimulates the expressions of a variety of genes including those related to angiogenesis, apoptosis and endoplasmic reticulum (ER) stress response. Here we show a close correlation between metastatic potential and the resistance to hypoxia- and ER st...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1209128
更新日期:2006-02-09 00:00:00
abstract::The anti-p185(her2/neu) peptidomimetic (AHNP) is a small exo-cyclic peptide derived from the anti-p185(her2/neu) rhumAb 4D5 (h4D5). AHNP mimics many but not all of the antitumor characteristics exhibited by h4D5. However, the pharmacokinetic profiles of AHNP are less than optimal for therapeutic or diagnostic purposes...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1209745
更新日期:2006-12-14 00:00:00
abstract::Terminal differentiation of skeletal myoblasts is accompanied by down-regulation of vimentin and beta-, gamma-actins and up-regulation of desmin and sarcomeric alpha-actin(s). To investigate whether the normal decline in expression of vimentin and beta-, gamma-actins was coupled to withdrawal of proliferating myoblast...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1989-07-01 00:00:00