Hide metadata

dc.date.accessioned2021-02-27T20:51:23Z
dc.date.available2021-02-27T20:51:23Z
dc.date.created2021-02-01T14:53:59Z
dc.date.issued2020
dc.identifier.citationSmeby, Jørgen Kryeziu, Kushtrim Berg, Kaja Christine Graue Eilertsen, Ina Andrassy Eide, Peter Andreas Wold Johannessen, Bjarne Guren, Marianne Nesbakken, Arild Bruun, Jarle Lothe, Ragnhild A Sveen, Anita . Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity. EBioMedicine. 2020, 59:102923, 1-13
dc.identifier.urihttp://hdl.handle.net/10852/83604
dc.description.abstractBackground PARP inhibitors are active in various tumour types beyond BRCA-mutant cancers, but their activity and molecular correlates in colorectal cancer (CRC) are not well studied. Methods Mutations and genome-wide mutational patterns associated with homologous recombination deficiency (HRD) were investigated in 255 primary CRCs with whole-exome sequencing and/or DNA copy number data. Efficacy of five PARP inhibitors and their molecular correlates were evaluated in 93 CRC cell lines partly annotated with mutational-, DNA copy number-, and/or gene expression profiles. Post-treatment gene expression profiling and specific protein expression analyses were performed in two pairs of PARP inhibitor sensitive and resistant cell lines. Findings A subset of microsatellite stable (MSS) CRCs had truncating mutations in homologous recombination-related genes, but these were not associated with genomic signatures of HRD. Eight CRC cell lines (9%) were sensitive to PARP inhibition, but sensitivity was not predicted by HRD-related genomic and transcriptomic signatures. In contrast, drug sensitivity in MSS cell lines was strongly associated with TP53 wild-type status (odds ratio 15.7, p = 0.023) and TP53-related expression signatures. Increased downstream TP53 activity was among the primary response mechanisms, and TP53 inhibition antagonized the effect of PARP inhibitors. Wild-type TP53-mediated suppression of RAD51 was identified as a possible mechanism of action for sensitivity to PARP inhibition. Interpretation PARP inhibitors are active in a subset of CRC cell lines and preserved TP53 function may increase the likelihood of response.
dc.languageEN
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleMolecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity
dc.typeJournal article
dc.creator.authorSmeby, Jørgen
dc.creator.authorKryeziu, Kushtrim
dc.creator.authorBerg, Kaja Christine Graue
dc.creator.authorEilertsen, Ina Andrassy
dc.creator.authorEide, Peter Andreas Wold
dc.creator.authorJohannessen, Bjarne
dc.creator.authorGuren, Marianne
dc.creator.authorNesbakken, Arild
dc.creator.authorBruun, Jarle
dc.creator.authorLothe, Ragnhild A
dc.creator.authorSveen, Anita
cristin.unitcode185,53,49,0
cristin.unitnameKreftklinikken
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1
dc.identifier.cristin1885207
dc.identifier.bibliographiccitationinfo:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=EBioMedicine&rft.volume=59:102923&rft.spage=1&rft.date=2020
dc.identifier.jtitleEBioMedicine
dc.identifier.volume59
dc.identifier.doihttps://doi.org/10.1016/j.ebiom.2020.102923
dc.identifier.urnURN:NBN:no-86331
dc.type.documentTidsskriftartikkel
dc.type.peerreviewedPeer reviewed
dc.source.issn2352-3964
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/83604/4/10.1016.j.ebiom.2020.102923.pdf
dc.type.versionPublishedVersion
cristin.articleid102923


Files in this item

Appears in the following Collection

Hide metadata

Attribution-NonCommercial-NoDerivatives 4.0 International
This item's license is: Attribution-NonCommercial-NoDerivatives 4.0 International