BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance

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dc.contributor.authorNesic, K.
dc.contributor.authorKrais, J.J.
dc.contributor.authorWang, Y.
dc.contributor.authorVandenberg, C.J.
dc.contributor.authorPatel, P.
dc.contributor.authorCai, K.Q.
dc.contributor.authorKwan, T.
dc.contributor.authorLieschke, E.
dc.contributor.authorHo, G.Y.
dc.contributor.authorBarker, H.E.
dc.contributor.authorBedo, J.
dc.contributor.authorCasadei, S.
dc.contributor.authorFarrell, A.
dc.contributor.authorRadke, M.
dc.contributor.authorShield-Artin, K.
dc.contributor.authorPenington, J.S.
dc.contributor.authorGeissler, F.
dc.contributor.authorKyran, E.
dc.contributor.authorBetsch, R.
dc.contributor.authorXu, L.
dc.contributor.authoret al.
dc.date.issued2024
dc.description.abstractPARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and postchemotherapy/ PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials. Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene’s reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations
dc.description.statementofresponsibilityKsenija Nesic, John J. Krais, Yifan Wang, Cassandra J. Vandenberg, Pooja Patel, Kathy Q. Cai, Tanya Kwan, Elizabeth Lieschke, Gwo, Yaw Ho, Holly E. Barker, Justin Bedo, Silvia Casadei, Andrew Farrell, Marc Radke, Kristy Shield, Artin, Jocelyn S. Penington, Franziska Geissler, Elizabeth Kyran, Robert Betsch, Lijun Xu, Fan Zhang, Alexander Dobrovic, Inger Olesen, Rebecca Kristeleit, Amit Oza, Iain McNeish, Gayanie Ratnayake, Nadia Traficante, Australian Ovarian Cancer Study, Anna DeFazio, David D. L. Bowtell, Thomas C. Harding, Kevin Lin, Elizabeth M. Swisher, Olga Kondrashova, Clare L. Scott, Neil Johnson, and Matthew J. Wakefield. (Consortia: Australian Ovarian Cancer Study (AOCS), G. Chenevix-Trench ... K. Oehler, ... T. Dodd ... K. Pittman ... et al.)
dc.identifier.citationMolecular Cancer, 2024; 23(1):158-1-158-10
dc.identifier.doi10.1186/s12943-024-02048-1
dc.identifier.issn1476-4598
dc.identifier.issn1476-4598
dc.identifier.orcidOehler, M.K. [0000-0002-2651-5913]
dc.identifier.urihttps://hdl.handle.net/2440/147829
dc.language.isoen
dc.publisherBMC
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1062702
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2009783
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2008631
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/199600
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/400413
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/400281
dc.rights© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
dc.source.urihttps://doi.org/10.1186/s12943-024-02048-1
dc.subjectBRCA1 secondary splice‑site mutations; exon‑skipping and PARP inhibitor resistance
dc.subject.meshHumans
dc.subject.meshPoly(ADP-ribose) Polymerase Inhibitors
dc.subject.meshExons
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshBRCA1 Protein
dc.subject.meshFemale
dc.subject.meshAnimals
dc.subject.meshMice
dc.subject.meshOvarian Neoplasms
dc.subject.meshRNA Splice Sites
dc.subject.meshMutation
dc.subject.meshBreast Neoplasms
dc.subject.meshXenograft Model Antitumor Assays
dc.subject.meshCell Line, Tumor
dc.titleBRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance
dc.typeJournal article
pubs.publication-statusPublished

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