dc.date.accessioned | 2021-02-27T20:51:23Z | |
dc.date.available | 2021-02-27T20:51:23Z | |
dc.date.created | 2021-02-01T14:53:59Z | |
dc.date.issued | 2020 | |
dc.identifier.citation | Smeby, 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.uri | http://hdl.handle.net/10852/83604 | |
dc.description.abstract | Background
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.language | EN | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.title | Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity | |
dc.type | Journal article | |
dc.creator.author | Smeby, Jørgen | |
dc.creator.author | Kryeziu, Kushtrim | |
dc.creator.author | Berg, Kaja Christine Graue | |
dc.creator.author | Eilertsen, Ina Andrassy | |
dc.creator.author | Eide, Peter Andreas Wold | |
dc.creator.author | Johannessen, Bjarne | |
dc.creator.author | Guren, Marianne | |
dc.creator.author | Nesbakken, Arild | |
dc.creator.author | Bruun, Jarle | |
dc.creator.author | Lothe, Ragnhild A | |
dc.creator.author | Sveen, Anita | |
cristin.unitcode | 185,53,49,0 | |
cristin.unitname | Kreftklinikken | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |
dc.identifier.cristin | 1885207 | |
dc.identifier.bibliographiccitation | info: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.jtitle | EBioMedicine | |
dc.identifier.volume | 59 | |
dc.identifier.doi | https://doi.org/10.1016/j.ebiom.2020.102923 | |
dc.identifier.urn | URN:NBN:no-86331 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 2352-3964 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/83604/4/10.1016.j.ebiom.2020.102923.pdf | |
dc.type.version | PublishedVersion | |
cristin.articleid | 102923 | |