Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division.


BACKGROUND:Chromosomal instability (CIN) is a common trait of cancer characterised by the continuous gain and loss of chromosomes during mitosis. Excessive levels of CIN can suppress tumour growth, providing a possible therapeutic strategy. The Mps1/TTK kinase has been one of the prime targets to explore this concept, and indeed Mps1 inhibitors synergise with the spindle poison docetaxel in inhibiting the growth of tumours in mice. METHODS:To investigate how the combination of docetaxel and a Mps1 inhibitor (Cpd-5) promote tumour cell death, we treated mice transplanted with BRCA1-/-;TP53-/- mammary tumours with docetaxel and/or Cpd-5. The tumours were analysed regarding their histopathology, chromosome segregation errors, copy number variations and cell death to understand the mechanism of action of the drug combination. RESULTS:The enhanced efficacy of combining an Mps1 inhibitor with clinically relevant doses of docetaxel is associated with an increase in multipolar anaphases, aberrant nuclear morphologies and cell death. Tumours treated with docetaxel and Cpd-5 displayed more genomic deviations, indicating that chromosome stability is affected mostly in the combinatorial treatment. CONCLUSIONS:Our study shows that the synergy between taxanes and Mps1 inhibitors depends on increased errors in cell division, allowing further optimisation of this treatment regimen for cancer therapy.


Br J Cancer


Maia ARR,Linder S,Song JY,Vaarting C,Boon U,Pritchard CEJ,Velds A,Huijbers IJ,van Tellingen O,Jonkers J,Medema RH




Has Abstract


2018-06-01 00:00:00














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    abstract:BACKGROUND:OCT3/4 (POU5F1) is an established diagnostic immunohistochemical marker for specific histological variants of human malignant germ cell tumours (GCTs), including the seminomatous types and the stem cell component of non-seminomas, known as embryonal carcinoma. OCT3/4 is crucial for the regulation of pluripot...

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    pub_type: 杂志文章


    authors: Rijlaarsdam MA,van Herk HA,Gillis AJ,Stoop H,Jenster G,Martens J,van Leenders GJ,Dinjens W,Hoogland AM,Timmermans M,Looijenga LH

    更新日期:2011-09-06 00:00:00

  • Clinical value of R-spondins in triple-negative and metaplastic breast cancers.

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    journal_title:British journal of cancer

    pub_type: 杂志文章


    authors: Coussy F,Lallemand F,Vacher S,Schnitzler A,Chemlali W,Caly M,Nicolas A,Richon S,Meseure D,El Botty R,De-Plater L,Fuhrmann L,Dubois T,Roman-Roman S,Dangles-Marie V,Marangoni E,Bièche I

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  • Interaction of carcinogenic metals with tissue and body fluids.

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    journal_title:British journal of cancer

    pub_type: 杂志文章


    authors: Weinzierl SM,Webb M

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  • Validation of a novel diagnostic standard in HPV-positive oropharyngeal squamous cell carcinoma.

    abstract:BACKGROUND:Human papillomavirus (HPV) testing in oropharyngeal squamous cell carcinoma (OPSCC) is now advocated. Demonstration of transcriptionally active high-risk HPV (HR-HPV) in fresh tumour tissue is considered to be the analytical 'gold standard'. Clinical testing has focused on formalin-fixed paraffin-embedded (F...

    journal_title:British journal of cancer

    pub_type: 杂志文章


    authors: Schache AG,Liloglou T,Risk JM,Jones TM,Ma XJ,Wang H,Bui S,Luo Y,Sloan P,Shaw RJ,Robinson M

    更新日期:2013-04-02 00:00:00

  • Multiple gene expression analysis reveals distinct differences between G2 and G3 stage breast cancers, and correlations of PKC eta with MDR1, MRP and LRP gene expression.

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    journal_title:British journal of cancer

    pub_type: 杂志文章


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    journal_title:British journal of cancer

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    authors: Ono K,Ishihara M,Ishikawa K,Ozeki Y,Deguchi H,Sato M,Hashimoto H,Saito Y,Yura H,Kurita A,Maehara T

    更新日期:2002-06-05 00:00:00

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    更新日期:2012-02-28 00:00:00

  • Long-term survival after treatment for Hodgkin's disease (1973-2002): improved survival with successive 10-year cohorts.

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    authors: Bessell EM,Bouliotis G,Armstrong S,Baddeley J,Haynes AP,O'Connor S,Nicholls-Elliott H,Bradley M

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    journal_title:British journal of cancer

    pub_type: 杂志文章


    authors: Ridge SA,Sludden J,Wei X,Sapone A,Brown O,Hardy S,Canney P,Fernandez-Salguero P,Gonzalez FJ,Cassidy J,McLeod HL

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    journal_title:British journal of cancer

    pub_type: 杂志文章


    authors: Mak TW,Aye MT,Messner H,Sheinin R,Till JE,McCulloch EA

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    pub_type: 杂志文章


    authors: Beskow C,Kanter L,Holgersson A,Nilsson B,Frankendal B,Avall-Lundqvist E,Lewensohn R

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    authors: Basso M,Strippoli A,Orlandi A,Martini M,Calegari MA,Schinzari G,Di Salvatore M,Cenci T,Cassano A,Larocca LM,Barone C

    更新日期:2013-01-15 00:00:00

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    authors: Courtenay VD,Selby PJ,Smith IE,Mills J,Peckham MJ

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    authors: Ota E,Abe Y,Oshika Y,Ozeki Y,Iwasaki M,Inoue H,Yamazaki H,Ueyama Y,Takagi K,Ogata T

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    authors: Jenkins V,Shilling V,Deutsch G,Bloomfield D,Morris R,Allan S,Bishop H,Hodson N,Mitra S,Sadler G,Shah E,Stein R,Whitehead S,Winstanley J

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    authors: Rak JW,McEachern D,Miller FR

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    journal_title:British journal of cancer

    pub_type: 杂志文章


    authors: Vatten LJ,Kvinnsland S

    更新日期:1990-06-01 00:00:00

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    journal_title:British journal of cancer

    pub_type: 杂志文章


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    journal_title:British journal of cancer

    pub_type: 杂志文章


    authors: Merrick A,Errington F,Milward K,O'Donnell D,Harrington K,Bateman A,Pandha H,Vile R,Morrison E,Selby P,Melcher A

    更新日期:2005-04-25 00:00:00

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    journal_title:British journal of cancer

    pub_type: 杂志文章


    authors: Bougnoux P,Germain E,Chajès V,Hubert B,Lhuillery C,Le Floch O,Body G,Calais G

    更新日期:1999-04-01 00:00:00

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    journal_title:British journal of cancer

    pub_type: 杂志文章


    authors: Qin B,Zou S,Li K,Wang H,Wei W,Zhang B,Xiao L,Choi HH,Tang Q,Huang D,Liu Q,Pan Q,Meng M,Fang L,Lee MH

    更新日期:2020-05-01 00:00:00

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    journal_title:British journal of cancer

    pub_type: 杂志文章


    authors: Price EA,Coombe DR,Murray JC

    更新日期:1996-12-01 00:00:00