Cotargeting BET proteins overcomes resistance arising from PI3K/mTOR blockade-induced protumorigenic senescence in colorectal cancer.


:Therapeutics targeting the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway initially produce potent antitumor effects, but resistance frequently occurs. Using a phosphoproteome analysis, we found that colorectal cancer (CRC) cells exhibit resistance against PI3K/mTOR inhibition through feedback activation of multiple receptor tyrosine kinases, and their downstream focal adhesion kinase, Src and extracellular signal-regulated kinases signaling. Unexpectedly, PI3K/mTOR blockade causes senescence, mediated by the activation of the stress kinase p38. The senescent cancer cells induce the secretion of various cytokines and this senescence-associated secretome increases migration and invasion capabilities of CRC cells. We found that cotargeting PI3K/mTOR and bromodomain and extra-terminal domain can suppress activation of many oncogenic kinases involved in resistance to the PI3K/mTOR inhibition, induce cell death in vitro and tumor regression in vivo, and further prolong the survival of xenograft models. Our findings provide a rationale for a novel therapeutic strategy to overcome resistance to the PI3K/mTOR inhibitors in CRC.


Int J Cancer


Lee HS,Lee S,Cho KH




Has Abstract


2020-11-15 00:00:00












  • Relationship of SNCG, S100A4, S100A9 and LCN2 gene expression and DNA methylation in bladder cancer.

    abstract::Microarray analysis of paired cultures of normal and cancerous urothelial cells revealed differences in cytokeratin and adhesion gene expression. Normal cells expressed autocrine growth factor genes more strongly whereas carcinoma cells were distinguished by concomitant expression of urothelial and epidermal different...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Dokun OY,Florl AR,Seifert HH,Wolff I,Schulz WA

    更新日期:2008-12-15 00:00:00

  • A prognostic classifier consisting of 17 circulating cytokines is a novel predictor of overall survival for metastatic colorectal cancer patients.

    abstract::We aimed to determine the prognostic values of 39 circulating cytokines in Chinese patients with metastatic colorectal cancer (CRC) and to develop a novel cytokine-based prognostic classifier (CBPC) for prognostic prediction. A total of 176 patients were divided into two cohorts based on the date of first-line chemoth...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Chen ZY,He WZ,Peng LX,Jia WH,Guo RP,Xia LP,Qian CN

    更新日期:2015-02-01 00:00:00

  • Treatment of Burkitt's lymphoma: randomized clinical trial of single-agent versus combination chemotherapy.

    abstract::A randomized clinical trial designed to compare the effectiveness of cytoxan (CTX) alone versus a combination consisting of CTX, vincristine (Oncovin) and methotrexate (COM) in the treatment of Burkitt's lymphoma (BL) was carried out. Nineteen patients were selected at random to receive CTX alone while 21 received COM...

    journal_title:International journal of cancer

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Olweny CL,Katongole-Mbidde E,Kaddu-Mukasa A,Atine I,Owor R,Lwanga S,Carswell W,Magrath IT

    更新日期:1976-04-15 00:00:00

  • PITX2: a promising predictive biomarker of patients' prognosis and chemoradioresistance in esophageal squamous cell carcinoma.

    abstract::The paired-like homeodomain transcription factor 2 (PITX2), a downstream effector of wnt/β-catenin signaling, is well known to play critical role during normal embryonic development. However, the possible involvement of PITX2 in human tumorigenesis remains unclear. In this study, we extend its function in human esopha...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Zhang JX,Tong ZT,Yang L,Wang F,Chai HP,Zhang F,Xie MR,Zhang AL,Wu LM,Hong H,Yin L,Wang H,Wang HY,Zhao Y

    更新日期:2013-06-01 00:00:00

  • Cancer incidence in a cohort of Ontario and Quebec women having bilateral breast augmentation.

    abstract::The possibility that women, who receive breast implants for cosmetic purposes, have increased long-term risks of developing cancer continues to be debated. The objective of our study was to prospectively examine cancer incidence among women who received breast implants. A cohort was assembled of 24,558 women, 18 years...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Brisson J,Holowaty EJ,Villeneuve PJ,Xie L,Ugnat AM,Latulippe L,Mao Y

    更新日期:2006-06-01 00:00:00

  • Enzymatic oxidation products of spermine induce greater cytotoxic effects on human multidrug-resistant colon carcinoma cells (LoVo) than on their wild-type counterparts.

    abstract::The occurrence of resistance to cytotoxic agents in tumor cells, associated with several phenotypic alterations, is one of the major obstacles to successful anticancer chemotherapy. A new strategy to overcome MDR of human cancer cells was studied, using BSAO, which generates cytotoxic products from spermine, H(2)O(2) ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Calcabrini A,Arancia G,Marra M,Crateri P,Befani O,Martone A,Agostinelli E

    更新日期:2002-05-01 00:00:00

  • Cost of decentralized CAR T-cell production in an academic nonprofit setting.

    abstract::Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy with high acquisition costs, and it has raised concerns about affordability and sustainability in many countries. Furthermore, the current centralized production paradigm for the T cells is less than satisfactory. Therefore, several countries ...

    journal_title:International journal of cancer

    pub_type: 杂志文章,评审


    authors: Ran T,Eichmüller SB,Schmidt P,Schlander M

    更新日期:2020-12-15 00:00:00

  • Analysis of acute-phase proteins, AHSG, C3, CLI, HP and SAA, reveals distinctive expression patterns associated with breast, colorectal and lung cancer.

    abstract::Early detection, clinical management and disease recurrence monitoring are critical areas in cancer treatment in which specific biomarker panels are likely to be very important in each of these key areas. We have previously demonstrated that levels of alpha-2-heremans-schmid-glycoprotein (AHSG), complement component C...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Dowling P,Clarke C,Hennessy K,Torralbo-Lopez B,Ballot J,Crown J,Kiernan I,O'Byrne KJ,Kennedy MJ,Lynch V,Clynes M

    更新日期:2012-08-15 00:00:00

  • IGFBP-3 prolongs the p53 response and enhances apoptosis following UV irradiation.

    abstract::Neoplastic transformation is characterised by an imbalance in favour of cell growth over programmed cell death (apoptosis). The tumour-suppressor gene p53, responsible for maintaining cell-cycle control, is mutated in the majority of human cancers. Loss of function of the target genes of p53 are therefore important in...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Hollowood AD,Lai T,Perks CM,Newcomb PV,Alderson D,Holly JM

    更新日期:2000-11-01 00:00:00

  • Human melanoma-specific oncofetal antigen defined by a mouse monoclonal antibody.

    abstract::140.240, an IgG2a mouse monoclonal antibody raised against a cultured human melanoma cell line, was highly specific for melanoma cells as determined by direct and absorption analyses in a mixed hemadsorption assay. Supernatants of doubly cloned hybridomas producing antibody 140.240 reacted with all cultured and fresh ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Liao SK,Clarke BJ,Khosravi M,Kwong PC,Brickenden A,Dent PB

    更新日期:1982-11-15 00:00:00

  • Lipid peroxidation and DNA adduct formation in lymphocytes of premenopausal women: Role of estrogen metabolites and fatty acid intake.

    abstract::A diet high in linoleic acid (an ω-6 PUFA) increased the formation of miscoding etheno (ε)--DNA adducts in WBC-DNA of women, but not in men (Nair et al., Cancer Epidemiol Biomark Prev 1997;6:597-601). This gender specificity could result from an interaction between ω-6 PUFA intake and estrogen catabolism, via redox-cy...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Sun X,Nair J,Linseisen J,Owen RW,Bartsch H

    更新日期:2012-11-01 00:00:00

  • Combination therapy of oncolytic herpes simplex virus HF10 and bevacizumab against experimental model of human breast carcinoma xenograft.

    abstract::Breast cancer is one of the most common and feared cancers faced by women. The prognosis of patients with advanced or recurrent breast cancer remains poor despite refinements in multimodality therapies involving chemotherapeutic and hormonal agents. Multimodal therapy with more specific and effective strategy is urgen...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Tan G,Kasuya H,Sahin TT,Yamamura K,Wu Z,Koide Y,Hotta Y,Shikano T,Yamada S,Kanzaki A,Fujii T,Sugimoto H,Nomoto S,Nishikawa Y,Tanaka M,Tsurumaru N,Kuwahara T,Fukuda S,Ichinose T,Kikumori T,Takeda S,Nakao A,Kode

    更新日期:2015-04-01 00:00:00

  • Pregnancy outcomes in childhood cancer survivors: probable effects of abdominal irradiation.

    abstract::A postal survey addressed to 2,083 general practitioners of childhood cancer survivors of reproductive age has revealed that females having undergone direct abdominal irradiation (exposed), particularly for Wilms' tumour, have an increased risk of several adverse pregnancy outcomes as compared with female survivors of...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Hawkins MM,Smith RA

    更新日期:1989-03-15 00:00:00

  • Signal processing in migrating T24 human bladder carcinoma cells: role of the autocrine interleukin-8 loop.

    abstract::T24 human bladder carcinoma cells reveal a high locomotor activity (70% locomoting cells) within a 3-dimensional collagen matrix. This high migratory activity is induced by an autocrine engagement of the interleukin-8 receptor A, as was shown by antibodies neutralizing the secreted interleukin-8. Treatment of the cell...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Lang K,Niggemann B,Zanker KS,Entschladen F

    更新日期:2002-06-10 00:00:00

  • Several genes encoding ribosomal proteins are over-expressed in prostate-cancer cell lines: confirmation of L7a and L37 over-expression in prostate-cancer tissue samples.

    abstract::A cDNA library specific for mRNA over-expressed in prostate cancer was generated by subtractive hybridization of transcripts originating from prostatic hyperplasia and cancer tissues. cDNA encoding ribosomal proteins L4, L5, L7a, L23a, L30, L37, S14 and S18 was found to be present among 100 analyzed clones. Levels of ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Vaarala MH,Porvari KS,Kyllönen AP,Mustonen MV,Lukkarinen O,Vihko PT

    更新日期:1998-09-25 00:00:00

  • Body size and composition and colon cancer risk in women.

    abstract::Studies of colon cancer risk in males have reported strong positive associations with obesity, particularly with central adiposity. The association has been weaker and less consistent for women. In a prospective cohort study of women, body measurements were taken directly; fat mass and fat-free mass being estimated by...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: MacInnis RJ,English DR,Hopper JL,Gertig DM,Haydon AM,Giles GG

    更新日期:2006-03-15 00:00:00

  • Cross-sectional study of Opisthorchis viverrini infection and cholangiocarcinoma in communities within a high-risk area in northeast Thailand.

    abstract::We describe an innovative strategy to quantify risk of cancer associated with varying levels of exposure to chronic parasitic infection through the identification of asymptomatic cases of cholangiocarcinoma within a population-based survey of Opisthorchis viverrini infection. Stool samples from 12,311 adults over age ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Haswell-Elkins MR,Mairiang E,Mairiang P,Chaiyakum J,Chamadol N,Loapaiboon V,Sithithaworn P,Elkins DB

    更新日期:1994-11-15 00:00:00

  • Chromosome 3p24-26 and 3p22-12 loss in human prostatic adenocarcinoma.

    abstract::Identification of loss of heterozygosity on specific genetic loci is crucial for understanding the pathogenesis of prostate cancer at the molecular level. This is especially important because the deleted regions may contain putative tumor suppressor genes. Chromosome 3p loss appears to be frequently associated with va...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Dahiya R,McCarville J,Hu W,Lee C,Chui RM,Kaur G,Deng G

    更新日期:1997-03-28 00:00:00

  • BRCA1 mutation analysis in 83 Spanish breast and breast/ovarian cancer families.

    abstract::A group of 83 Spanish BC/OC families were analysed for BRCA1 germ-line mutations. Analysis of the entire coding sequence was carried out by SSCP and PTT. We identified 5 frameshift mutations: 185delAG (2 times), 189insTGTC, 1241delAC, and 5537delA and 3 missense mutations in BRCA1: 330A > G, 1240C > T, and 5263G > A. ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Díez O,Cortés J,Domènech M,Brunet J,Del Río E,Pericay C,Sanz J,Alonso C,Baiget M

    更新日期:1999-11-12 00:00:00

  • Immunohistologic expression of blood-group antigens in normal human gastrointestinal tract and colonic carcinoma.

    abstract::A panel of 7 mouse monoclonal antibodies and the lectin from Ulex europeus, detecting blood-group-related antigens of the ABH and Lewis systems, have been used to define the distribution of these antigenic structures within the human gastrointestinal tract, and to characterize their expression and modulation in colore...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Cordon-Cardo C,Lloyd KO,Sakamoto J,McGroarty ME,Old LJ,Melamed MR

    更新日期:1986-05-15 00:00:00

  • Tobacco and occupation as risk factors in bladder cancer: a case-control study in southern Belgium.

    abstract::A pilot case-control study on bladder cancer, with population-based controls matched for each of 74 cases, has been conducted in two industrial areas of Southern Belgium in order to analyze the influence of tobacco use and occupation. Observed bladder cancer risk for smokers is more than 5 times higher than that for n...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Schifflers E,Jamart J,Renard V

    更新日期:1987-03-15 00:00:00

  • Occupational sun exposure and risk of melanoma according to anatomical site.

    abstract::Although sunburn and intermittent sun exposures are associated with increased melanoma risk, most studies have found null or inverse associations between occupational (more continuous pattern) sun exposure and melanoma risk. The association of melanoma with occupational sun exposure may differ according to anatomical ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Vuong K,McGeechan K,Armstrong BK,AMFS Investigators.,GEM Investigators.,Cust AE

    更新日期:2014-06-01 00:00:00

  • Ovarian cancer-derived copy number alterations signatures are prognostic in chemoradiotherapy-treated head and neck squamous cell carcinoma.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Essers PBM,van der Heijden M,Vossen D,de Roest RH,Leemans CR,Brakenhoff RH,van den Brekel MWM,Bartelink H,Verheij M,Vens C

    更新日期:2020-09-15 00:00:00

  • Trends in incidence and mortality of thyroid carcinoma in The Netherlands between 1989 and 2003: correlation with thyroid fine-needle aspiration cytology and thyroid surgery.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Netea-Maier RT,Aben KK,Casparie MK,den Heijer M,Grefte JM,Slootweg P,Hermus A

    更新日期:2008-10-01 00:00:00

  • Thymidylate synthase expression in circulating tumor cells: a new tool to predict 5-fluorouracil resistance in metastatic colorectal cancer patients.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Abdallah EA,Fanelli MF,Buim ME,Machado Netto MC,Gasparini Junior JL,Souza E Silva V,Dettino AL,Mingues NB,Romero JV,Ocea LM,Rocha BM,Alves VS,Araújo DV,Chinen LT

    更新日期:2015-09-15 00:00:00

  • A yeast two-hybrid system using Sp17 identified Ropporin as a novel cancer-testis antigen in hematologic malignancies.

    abstract::Since most intracellular proteins are expressed with their ligands, ligands of cancer-testis (CT) antigens may also be CT in their distribution. Applying Sperm protein 17 (Sp17) as the bait in a yeast 2-hybrid system of a testicular cDNA library, 17 interacting clones were isolated and all encoded Ropporin, a spermato...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Li Z,Li W,Meklat F,Wang Z,Zhang J,Zhang Y,Lim SH

    更新日期:2007-10-01 00:00:00

  • Elevated expression of eIF4E in confined early breast cancer lesions: possible role of hypoxia.

    abstract::The translation-initiation factor eIF4E is rate-limiting for protein synthesis, and its over-expression results in oncogenic transformation of mammalian cells. eIF4E facilitates the synthesis of several powerful tumor angiogenic factors (FGF-2 and VEGF) by selectively enhancing their translation. In breast carcinomas,...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: DeFatta RJ,Turbat-Herrera EA,Li BD,Anderson W,De Benedetti A

    更新日期:1999-02-09 00:00:00

  • Acrylamide exposure measured by food frequency questionnaire and hemoglobin adduct levels and prostate cancer risk in the Cancer of the Prostate in Sweden Study.

    abstract::Acrylamide, a probable human carcinogen, is formed during the cooking of many commonly consumed foods. Data are scant on whether dietary acrylamide represents an important cancer risk in humans. We studied the association between acrylamide and prostate cancer risk using 2 measures of acrylamide exposure: intake from ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Wilson KM,Bälter K,Adami HO,Grönberg H,Vikström AC,Paulsson B,Törnqvist M,Mucci LA

    更新日期:2009-05-15 00:00:00

  • Relation of smoking to breast cancer by estrogen receptor status.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Morabia A,Bernstein M,Ruiz J,Héritier S,Diebold Berger S,Borisch B

    更新日期:1998-01-30 00:00:00

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    abstract::Claudin7 (cld7) is a cancer-initiating cell (CIC) marker in gastrointestinal tumors, a cld7-knockdown (kd) being accompanied by loss of tumor progression. Tumor exosomes (TEX) restoring CIC activities, we explored the contribution of cld7. This became particularly interesting, as tight junction (TJ)- and glycolipid-en...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Kyuno D,Zhao K,Schnölzer M,Provaznik J,Hackert T,Zöller M

    更新日期:2019-10-15 00:00:00