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dc.contributor.authorGeorgiou, Marina
dc.contributor.authorNtavelou, Panagiota
dc.contributor.authorStokes, William
dc.contributor.authorRoy, Rajat
dc.contributor.authorMaher, Geoffrey J
dc.contributor.authorStoilova, Tsvetana
dc.contributor.authorChoo, Josephine AMY
dc.contributor.authorRakhit, Callum P
dc.contributor.authorMartins, Miguel
dc.contributor.authorAjuh, Paul
dc.contributor.authorHorowitz, Neil
dc.contributor.authorBerkowitz, Ross S
dc.contributor.authorElias, Kevin
dc.contributor.authorSeckl, Michael J
dc.contributor.authorPardo, Olivier E
dc.date.accessioned2022-06-07T08:11:03Z
dc.date.available2022-06-07T08:11:03Z
dc.date.issued2022-04
dc.date.submitted2021-07-26
dc.identifier.issn0950-9232
dc.identifier.others41388-022-02251-8
dc.identifier.other2251
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337747
dc.descriptionFunder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265
dc.descriptionFunder: Cancer Treatment and Research Trust
dc.descriptionFunder: Donald P Goldstein,MD Trophoblastic Tumor Registry Endowment Dyett Family Trophoblastic Disease Research and Registry Endowment
dc.description.abstractLow-risk gestational trophoblastic neoplasia including choriocarcinoma is often effectively treated with Methotrexate (MTX) as a first line therapy. However, MTX resistance (MTX-R) occurs in at least ≈33% of cases. This can sometimes be salvaged with actinomycin-D but often requires more toxic combination chemotherapy. Moreover, additional therapy may be needed and, for high-risk patients, 5% still die from the multidrug-resistant disease. Consequently, new treatments that are less toxic and could reverse MTX-R are needed. Here, we compared the proteome/phosphoproteome of MTX-resistant and sensitive choriocarcinoma cells using quantitative mass-spectrometry to identify therapeutically actionable molecular changes associated with MTX-R. Bioinformatics analysis of the proteomic data identified cell cycle and DNA damage repair as major pathways associated with MTX-R. MTX-R choriocarcinoma cells undergo cell cycle delay in G1 phase that enables them to repair DNA damage more efficiently through non-homologous end joining in an ATR-dependent manner. Increased expression of cyclin-dependent kinase 4 (CDK4) and loss of p16Ink4a in resistant cells suggested that CDK4 inhibition may be a strategy to treat MTX-R choriocarcinoma. Indeed, inhibition of CDK4/6 using genetic silencing or the clinically relevant inhibitor, Palbociclib, induced growth inhibition both in vitro and in an orthotopic in vivo mouse model. Finally, targeting the ATR pathway, genetically or pharmacologically, re-sensitised resistant cells to MTX in vitro and potently prevented the growth of MTX-R tumours in vivo. In short, we identified two novel therapeutic strategies to tackle MTX-R choriocarcinoma that could rapidly be translated into the clinic.
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectArticle
dc.subject/631/67/1059/2326
dc.subject/631/67/1517
dc.subject/96/106
dc.subject/13/31
dc.subject/13/89
dc.subject/13/95
dc.subject/59
dc.subject/96
dc.subject/96/109
dc.subjectarticle
dc.titleATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma.
dc.typeArticle
dc.date.updated2022-06-07T08:11:02Z
prism.endingPage2554
prism.issueIdentifier18
prism.publicationNameOncogene
prism.startingPage2540
prism.volume41
dc.identifier.doi10.17863/CAM.85156
dcterms.dateAccepted2022-02-15
rioxxterms.versionofrecord10.1038/s41388-022-02251-8
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidMaher, Geoffrey J [0000-0001-7135-4824]
dc.contributor.orcidRakhit, Callum P [0000-0002-5185-7405]
dc.contributor.orcidSeckl, Michael J [0000-0003-4078-2599]
dc.contributor.orcidPardo, Olivier E [0000-0003-2223-1435]
dc.identifier.eissn1476-5594
cam.issuedOnline2022-03-18


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