Genetic targeting of B-RafV600E affects survival and proliferation and identifies selective agents against BRAF-mutant colorectal cancer cells.

Abstract:

BACKGROUND:Colorectal cancers carrying the B-Raf V600E-mutation are associated with a poor prognosis. The purpose of this study was to identify B-RafV600E-mediated traits of cancer cells in a genetic in vitro model and to assess the selective sensitization of B-RafV600E-mutant cancer cells towards therapeutic agents. METHODS:Somatic cell gene targeting was used to generate subclones of the colorectal cancer cell line RKO containing either wild-type or V600E-mutant B-Raf kinase. Cell-biologic analyses were performed in order to link cancer cell traits to the BRAF-mutant genotype. Subsequently, the corresponding tumor cell clones were characterized pharmacogenetically to identify therapeutic agents exhibiting selective sensitivity in B-RafV600E-mutant cells. RESULTS:Genetic targeting of mutant BRAF resulted in restoration of sensitivity to serum starvation-induced apoptosis and efficiently inhibited cell proliferation in the absence of growth factors. Among tested agents, the B-Raf inhibitor dabrafenib was found to induce a strong V600E-dependent shift in cell viability. In contrast, no differential sensitizing effect was observed for conventional chemotherapeutic agents (mitomycin C, oxaliplatin, paclitaxel, etoposide, 5-fluorouracil), nor for the targeted agents cetuximab, sorafenib, vemurafenib, RAF265, or for inhibition of PI3 kinase. Treatment with dabrafenib efficiently inhibited phosphorylation of the B-Raf downstream targets Mek 1/2 and Erk 1/2. CONCLUSION:Mutant BRAF alleles mediate self-sufficiency of growth signals and serum starvation-induced resistance to apoptosis. Targeting of the BRAF mutation leads to a loss of these hallmarks of cancer. Dabrafenib selectively inhibits cell viability in B-RafV600E mutant cancer cells.

journal_name

Mol Cancer

journal_title

Molecular cancer

authors

Hirschi B,Gallmeier E,Ziesch A,Marschall M,Kolligs FT

doi

10.1186/1476-4598-13-122

subject

Has Abstract

pub_date

2014-05-24 00:00:00

pages

122

issn

1476-4598

pii

1476-4598-13-122

journal_volume

13

pub_type

杂志文章
  • NSC114792, a novel small molecule identified through structure-based computational database screening, selectively inhibits JAK3.

    abstract:BACKGROUND:Human or animals lacking either JAK3 or the common gamma chain (gammac) expression display severe combined immunodeficiency disease, indicating the crucial role of JAK3 in T-cell development and the homeostasis of the immune system. JAK3 has also been suggested to contribute to the pathogenesis of tumorigene...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-9-36

    authors: Kim BH,Jee JG,Yin CH,Sandoval C,Jayabose S,Kitamura D,Bach EA,Baeg GH

    更新日期:2010-02-11 00:00:00

  • Functional studies of BCL11A: characterization of the conserved BCL11A-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells.

    abstract:BACKGROUND:Chromosomal aberrations of BCL11A at 2p16.1 have been reported in a variety of B-cell malignancies and its deficiency in mice leads to a profound block in B-cell development. RESULTS:Alternative pre-mRNA splicing of BCL11A produces multiple isoforms sharing a common N-terminus. The most abundant isoform we ...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-5-18

    authors: Liu H,Ippolito GC,Wall JK,Niu T,Probst L,Lee BS,Pulford K,Banham AH,Stockwin L,Shaffer AL,Staudt LM,Das C,Dyer MJ,Tucker PW

    更新日期:2006-05-16 00:00:00

  • Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity.

    abstract::Chimeric antigen receptor T (CAR-T) cell therapy is an emerging and effective cancer immunotherapy. Especially in hematological malignancies, CAR-T cells have achieved exciting results. Two Anti-CD19 CAR-T therapies have been approved for the treatment of CD19-positive leukemia or lymphoma. However, the application of...

    journal_title:Molecular cancer

    pub_type: 杂志文章,评审

    doi:10.1186/s12943-019-1057-4

    authors: Yu S,Yi M,Qin S,Wu K

    更新日期:2019-08-20 00:00:00

  • Regulation of Erk1/2 activation by osteopontin in PC3 human prostate cancer cells.

    abstract:BACKGROUND:Osteopontin (OPN) has been shown to play many roles in the progression of cancer. We have recently demonstrated the activation of Akt by OPN. Integrin-linked kinase and PI3-kinase are integral proteins in OPN/AKT pathway in PC3 cells. To investigate the role of the extracellular receptors in OPN signaling, w...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-9-260

    authors: Robertson BW,Bonsal L,Chellaiah MA

    更新日期:2010-09-26 00:00:00

  • Stromal ING1 expression induces a secretory phenotype and correlates with breast cancer patient survival.

    abstract:BACKGROUND:Previous studies have established that levels of the Inhibitor of Growth 1(ING1) tumor suppressor are reduced in a significant proportion of different cancer types. Here we analyzed levels of ING1 in breast cancer patients to determine its prognostic significance as a biomarker for breast cancer prognosis. ...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/s12943-015-0434-x

    authors: Thakur S,Nabbi A,Klimowicz A,Riabowol K

    更新日期:2015-08-27 00:00:00

  • Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy.

    abstract::Autophagy is a highly conserved catabolic process that mediates degradation of pernicious or dysfunctional cellular components, such as invasive pathogens, senescent proteins, and organelles. It can promote or suppress tumor development, so it is a "double-edged sword" in tumors that depends on the cell and tissue typ...

    journal_title:Molecular cancer

    pub_type: 杂志文章,评审

    doi:10.1186/s12943-019-1030-2

    authors: Chen HT,Liu H,Mao MJ,Tan Y,Mo XQ,Meng XJ,Cao MT,Zhong CY,Liu Y,Shan H,Jiang GM

    更新日期:2019-05-24 00:00:00

  • METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer.

    abstract:BACKGROUND:As one of the most frequent chemical modifications in eukaryotic mRNAs, N6-methyladenosine (m6A) modification exerts important effects on mRNA stability, splicing, and translation. Recently, the regulatory role of m6A in tumorigenesis has been increasingly recognized. However, dysregulation of m6A and its fu...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/s12943-019-1065-4

    authors: Yue B,Song C,Yang L,Cui R,Cheng X,Zhang Z,Zhao G

    更新日期:2019-10-13 00:00:00

  • PTEN inhibits BMI1 function independently of its phosphatase activity.

    abstract:BACKGROUND:PTEN is the second most mutated tumor suppressor gene other than p53. It suppresses tumorigenesis by dephosphorylating phosphatidylinositol (3,4,5)-triphosphate (PIP3) to phosphatidylinositol (4,5)-biphosphate (PIP2), thereby directly inhibiting phosphatidylinositol 3 kinase (PI3K)-mediated tumorigenic activ...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-8-98

    authors: Fan C,He L,Kapoor A,Rybak AP,De Melo J,Cutz JC,Tang D

    更新日期:2009-11-10 00:00:00

  • Role of the NLRP3 inflammasome in cancer.

    abstract::Inflammasomes are large intracellular multi-protein signalling complexes that are formed in the cytosolic compartment as an inflammatory immune response to endogenous danger signals. The formation of the inflammasome enables activation of an inflammatory protease caspase-1, pyroptosis initiation with the subsequent cl...

    journal_title:Molecular cancer

    pub_type: 杂志文章,评审

    doi:10.1186/s12943-018-0900-3

    authors: Moossavi M,Parsamanesh N,Bahrami A,Atkin SL,Sahebkar A

    更新日期:2018-11-17 00:00:00

  • Clinicopathological significance of stromal variables: angiogenesis, lymphangiogenesis, inflammatory infiltration, MMP and PINCH in colorectal carcinomas.

    abstract::Cancer research has mainly focused on alterations of genes and proteins in cancer cells themselves that result in either gain-of-function in oncogenes or loss-of-function in tumour-suppressor genes. However, stromal variables within or around tumours, including blood and lymph vessels, stromal cells and various protei...

    journal_title:Molecular cancer

    pub_type: 杂志文章,评审

    doi:10.1186/1476-4598-5-43

    authors: Sun XF,Zhang H

    更新日期:2006-10-06 00:00:00

  • Favorable outcome of patients with lung adenocarcinoma harboring POLE mutations and expressing high PD-L1.

    abstract::Mutations in polymerase ε (POLE) confer favorable prognosis and outcomes in various cancer types, but their role in non-small cell lung cancer (NSCLC) is unknown. Utilizing the data of 513 patients with adenocarcinoma (LUAD) and 497 patients with squamous cell carcinoma (LUSC) from The Cancer Genome Atlas (TCGA) cohor...

    journal_title:Molecular cancer

    pub_type: 信件

    doi:10.1186/s12943-018-0832-y

    authors: Liu L,Ruiz J,O'Neill SS,Grant SC,Petty WJ,Yang M,Chen K,Topaloglu U,Pasche B,Zhang W

    更新日期:2018-04-12 00:00:00

  • Combination treatment with ABT-737 and chloroquine in preclinical models of small cell lung cancer.

    abstract:BACKGROUND:New therapies are urgently needed for patients with small cell lung cancer (SCLC). Chemotherapy and targeted therapies, including the Bcl-2 inhibitor ABT-737, may induce tumor cell autophagy. Autophagy can promote survival of cancer cells under stress and comprise a pathway of escape from cytotoxic therapies...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-12-16

    authors: Zinn RL,Gardner EE,Dobromilskaya I,Murphy S,Marchionni L,Hann CL,Rudin CM

    更新日期:2013-03-02 00:00:00

  • Expression and function of hypoxia inducible factor-1 alpha in human melanoma under non-hypoxic conditions.

    abstract:BACKGROUND:Hypoxia inducible factor-1 alpha (HIF-1alpha) protein is rapidly degraded under normoxic conditions. When oxygen tensions fall HIF-1alpha protein stabilizes and transactivates genes involved in adaptation to hypoxic conditions. We have examined the normoxic expression of HIF-1alpha RNA and protein in normal ...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-8-104

    authors: Mills CN,Joshi SS,Niles RM

    更新日期:2009-11-17 00:00:00

  • PIWI-interacting RNA-36712 restrains breast cancer progression and chemoresistance by interaction with SEPW1 pseudogene SEPW1P RNA.

    abstract:BACKGROUND:Breast cancer is one of the most common malignancies and the major cause of cancer-related death in women. Although the importance of PIWI-interacting RNAs (piRNAs) in cancer has been increasingly recognized, few studies have been explored the functional mechanism of piRNAs in breast cancer development and p...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/s12943-019-0940-3

    authors: Tan L,Mai D,Zhang B,Jiang X,Zhang J,Bai R,Ye Y,Li M,Pan L,Su J,Zheng Y,Liu Z,Zuo Z,Zhao Q,Li X,Huang X,Yang J,Tan W,Zheng J,Lin D

    更新日期:2019-01-12 00:00:00

  • Emerging role of exosome-derived long non-coding RNAs in tumor microenvironment.

    abstract::Exosomes are extracellular vesicles released by many cell types and have been attributed for their roles in many diseases including cancer. Exosomes secreted by tumor cells and stromal cells are critical mediators of intercellular communication in tumor microenvironments. Long noncoding RNAs (lncRNAs) are selectively ...

    journal_title:Molecular cancer

    pub_type: 杂志文章,评审

    doi:10.1186/s12943-018-0831-z

    authors: Sun Z,Yang S,Zhou Q,Wang G,Song J,Li Z,Zhang Z,Xu J,Xia K,Chang Y,Liu J,Yuan W

    更新日期:2018-04-20 00:00:00

  • Nicotine-induced survival signaling in lung cancer cells is dependent on their p53 status while its down-regulation by curcumin is independent.

    abstract:BACKGROUND:Lung cancer is the most lethal cancer and almost 90% of lung cancer is due to cigarette smoking. Even though nicotine, one of the major ingredients of cigarette smoke and the causative agent for addiction, is not a carcinogen by itself, several investigators have shown that nicotine can induce cell prolifera...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-9-220

    authors: Puliyappadamba VT,Cheriyan VT,Thulasidasan AK,Bava SV,Vinod BS,Prabhu PR,Varghese R,Bevin A,Venugopal S,Anto RJ

    更新日期:2010-08-20 00:00:00

  • mRNA-to-protein translation in hypoxia.

    abstract::Cells respond to hypoxia by shifting cellular processes from general housekeeping functions to activating specialized hypoxia-response pathways. Oxygen plays an important role in generating ATP to maintain a productive rate of protein synthesis in normoxia. In hypoxia, the rate of the canonical protein synthesis pathw...

    journal_title:Molecular cancer

    pub_type: 杂志文章,评审

    doi:10.1186/s12943-019-0968-4

    authors: Chee NT,Lohse I,Brothers SP

    更新日期:2019-03-30 00:00:00

  • HCCS1-armed, quadruple-regulated oncolytic adenovirus specific for liver cancer as a cancer targeting gene-viro-therapy strategy.

    abstract:BACKGROUND:In previously published studies, oncolytic adenovirus-mediated gene therapy has produced good results in targeting cancer cells. However, safety and efficacy, the two most important aspects in cancer therapy, remain serious challenges. The specific expression or deletion of replication related genes in an ad...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-10-133

    authors: Xu HN,Huang WD,Cai Y,Ding M,Gu JF,Wei N,Sun LY,Cao X,Li HG,Zhang KJ,Liu XR,Liu XY

    更新日期:2011-11-01 00:00:00

  • MicroRNA-218 functions as a tumor suppressor in lung cancer by targeting IL-6/STAT3 and negatively correlates with poor prognosis.

    abstract:BACKGROUND:Aberrant expression of microRNAs in different human cancer types has been widely reported. MiR-218 acts as a tumor suppressor in diverse human cancer types impacting regulation of multiple genes in oncogenic pathways. Here, we evaluated the expression and function of miR-218 in human lung cancer and ALDH pos...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/s12943-017-0710-z

    authors: Yang Y,Ding L,Hu Q,Xia J,Sun J,Wang X,Xiong H,Gurbani D,Li L,Liu Y,Liu A

    更新日期:2017-08-22 00:00:00

  • Epigenetic aberrations and cancer.

    abstract::The correlation between epigenetic aberrations and disease underscores the importance of epigenetic mechanisms. Here, we review recent findings regarding chromatin modifications and their relevance to cancer. ...

    journal_title:Molecular cancer

    pub_type: 杂志文章,评审

    doi:10.1186/1476-4598-5-60

    authors: Ducasse M,Brown MA

    更新日期:2006-11-08 00:00:00

  • LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro.

    abstract:BACKGROUND:Relapse due to chemoresistant residual disease is a major cause of death in acute myelogenous leukemia (AML). The present study was undertaken to elucidate the molecular mechanisms of chemoresistance by comparing differential gene expression in blasts from patients with resistant relapsing AML and chemosensi...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-6-31

    authors: Huang TS,Myklebust LM,Kjarland E,Gjertsen BT,Pendino F,Bruserud Ø,Døskeland SO,Lillehaug JR

    更新日期:2007-04-23 00:00:00

  • Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis.

    abstract:BACKGROUND:Recently, it has been reported that long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2), a novel tumor suppressor, participates in regulating the carcinogenesis and suppresses tumor progression by sponging microRNAs (miRNAs). However, the expression and function of CASC2 in hepatocellular ...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/s12943-017-0702-z

    authors: Wang Y,Liu Z,Yao B,Li Q,Wang L,Wang C,Dou C,Xu M,Liu Q,Tu K

    更新日期:2017-07-17 00:00:00

  • Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2.

    abstract:BACKGROUND:Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and the biology of this cancer remains poorly understood. Recent evidence indicates that long non-coding RNAs (lncRNAs) are found to be dysregulated in a variety of cancers, including HCC. Taurine Up-regulated Gene...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/s12943-015-0431-0

    authors: Huang MD,Chen WM,Qi FZ,Sun M,Xu TP,Ma P,Shu YQ

    更新日期:2015-09-04 00:00:00

  • The circRNA circAGFG1 acts as a sponge of miR-195-5p to promote triple-negative breast cancer progression through regulating CCNE1 expression.

    abstract:BACKGROUND:In recent years, circular RNAs (circRNAs), a new star of non-coding RNA, have been emerged as vital regulators and gained much attention for involvement of initiation and progression of diverse kinds of human diseases, especially cancer. However, regulatory role, clinical significance and underlying mechanis...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/s12943-018-0933-7

    authors: Yang R,Xing L,Zheng X,Sun Y,Wang X,Chen J

    更新日期:2019-01-08 00:00:00

  • Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression.

    abstract:BACKGROUND:SKI and SnoN proteins have been shown to inhibit TGF-β signaling, acting both as transcriptional co-repressors in the cell nucleus, and as sequestrators of SMAD proteins in the cytoplasm. TGF-β, on the other hand, induces rapid, proteasome-mediated, degradation of both proteins. How elevated SKI and SnoN pro...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-10-2

    authors: Javelaud D,van Kempen L,Alexaki VI,Le Scolan E,Luo K,Mauviel A

    更新日期:2011-01-06 00:00:00

  • METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner.

    abstract:BACKGROUND:METTL3 is known to be involved in all stages in the life cycle of RNA. It affects the tumor formation by the regulation the m6A modification in the mRNAs of critical oncogenes or tumor suppressors. In bladder cancer, METTL3 could promote the bladder cancer progression via AFF4/NF-κB/MYC signaling network by ...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/s12943-019-1036-9

    authors: Han J,Wang JZ,Yang X,Yu H,Zhou R,Lu HC,Yuan WB,Lu JC,Zhou ZJ,Lu Q,Wei JF,Yang H

    更新日期:2019-06-22 00:00:00

  • Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes.

    abstract:BACKGROUND:The human cell cycle transcription factor FOXM1 is known to play a key role in regulating timely mitotic progression and accurate chromosomal segregation during cell division. Deregulation of FOXM1 has been linked to a majority of human cancers. We previously showed that FOXM1 was upregulated in basal cell c...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-9-45

    authors: Teh MT,Gemenetzidis E,Chaplin T,Young BD,Philpott MP

    更新日期:2010-02-26 00:00:00

  • Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells.

    abstract:BACKGROUND:Reovirus type 3 Dearing strain (ReoT3D) has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers. Its human safet...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/1476-4598-8-47

    authors: Sei S,Mussio JK,Yang QE,Nagashima K,Parchment RE,Coffey MC,Shoemaker RH,Tomaszewski JE

    更新日期:2009-07-14 00:00:00

  • Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N6-methyladenosine of Notch1.

    abstract:BACKGROUND:N6-methyladenosine (m6A) emerges as one of the most important modification of RNA. Bladder cancer is a common cancer type in developed countries, and hundreds of thousands of bladder cancer patients die every year. MATERIALS AND METHODS:There are various cells in bladder tumor bulk, and a small population c...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/s12943-019-1084-1

    authors: Gu C,Wang Z,Zhou N,Li G,Kou Y,Luo Y,Wang Y,Yang J,Tian F

    更新日期:2019-11-25 00:00:00

  • Oncogenic KRAS promotes malignant brain tumors in zebrafish.

    abstract:BACKGROUND:Zebrafish have been used as a vertebrate model to study human cancers such as melanoma, rhabdomyosarcoma, liver cancer, and leukemia as well as for high-throughput screening of small molecules of therapeutic value. However, they are just emerging as a model for human brain tumors, which are among the most de...

    journal_title:Molecular cancer

    pub_type: 杂志文章

    doi:10.1186/s12943-015-0288-2

    authors: Ju B,Chen W,Orr BA,Spitsbergen JM,Jia S,Eden CJ,Henson HE,Taylor MR

    更新日期:2015-02-03 00:00:00