BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance
BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance
Abstract BRCA1 splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out mutation-containing exons, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers of BRCA1 exon skipping remain undetermined. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for splice isoform expression and therapy response. This included a matched PDX pair derived from a patient pre-and post-chemotherapy/PARPi regimen. BRCA1 exon 11-deficient isoform expression was generally elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs), predicted in silico to drive exon skipping. Predictions were confirmed using qRT-PCR, RNA sequencing, western blots and BRCA1 minigene modelling. SSMs were also enriched in post-PARPi OC patient cohorts from the ARIEL2 and ARIEL4 clinical trials. We demonstrate that SSMs drive BRCA1 exon 11 skipping and PARPi resistance, and should be clinically monitored, along with frame-restoring secondary mutations.
Zhang Fan、Oza Amit、Ratnayake Gayanie、Lin Kevin、DeFazio Anna、Bowtell David D. L.、Harding Thomas C.、Swisher Elizabeth M.、Scott Clare L.、Shield-Artin Kristy、Kristeleit Rebecca、Wang Yifan、Patel Pooja、Nesic Ksenija、Penington Jocelyn S.、Vandenberg Cassandra J.、Barker Holly E.、Olesen Inger、Traficante Nadia、Radke Marc、Farrell Andrew、Ho Gwo-Yaw、Kondrashova Olga、Australian Ovarian Cancer Study、Johnson Neil、Kwan Tanya、Casadei Silvia、Geissler Franziska、Lieschke Elizabeth、Krais John J.、Wakefield Matthew J.、Dobrovic Alexander、Bedo Justin
University of Melbourne Department of SurgeryPrincess Margaret Cancer CenterRoyal Women?ˉs HospitalClovis Oncology Inc.The Daffodil Centre, The University of Sydney||The Westmead Institute for Medical Research||Department of Gynecological Oncology, Westmead HospitalSir Peter MacCallum Cancer Centre||Sir Peter MacCallum Department of Oncology, University of MelbourneClovis Oncology Inc.University of WashingtonThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of Melbourne||Royal Women?ˉs Hospital||Sir Peter MacCallum Cancer Centre||Sir Peter MacCallum Department of Oncology, University of Melbourne||Department of Obstetrics and Gynaecology, University of MelbourneThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of MelbourneDepartment of Oncology, Guys and St Thomas?ˉ NHS Foundation Trust||National Institute for Health Research, University College London Hospitals Clinical Research FacilityFox Chase Cancer CenterFox Chase Cancer CenterThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of MelbourneThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of MelbourneThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of MelbourneThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of MelbourneThe Andrew Love Cancer CentreSir Peter MacCallum Cancer Centre||Sir Peter MacCallum Department of Oncology, University of MelbourneUniversity of WashingtonThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of MelbourneSchool of Clinical Sciences, Monash UniversityQIMR Berghofer Medical Research InstituteFox Chase Cancer CenterClovis Oncology Inc.University of WashingtonThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of MelbourneThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of MelbourneFox Chase Cancer CenterThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of Melbourne||Department of Obstetrics and Gynaecology, University of MelbourneUniversity of Melbourne Department of SurgeryThe Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of Melbourne
医学研究方法肿瘤学基础医学
Zhang Fan,Oza Amit,Ratnayake Gayanie,Lin Kevin,DeFazio Anna,Bowtell David D. L.,Harding Thomas C.,Swisher Elizabeth M.,Scott Clare L.,Shield-Artin Kristy,Kristeleit Rebecca,Wang Yifan,Patel Pooja,Nesic Ksenija,Penington Jocelyn S.,Vandenberg Cassandra J.,Barker Holly E.,Olesen Inger,Traficante Nadia,Radke Marc,Farrell Andrew,Ho Gwo-Yaw,Kondrashova Olga,Australian Ovarian Cancer Study,Johnson Neil,Kwan Tanya,Casadei Silvia,Geissler Franziska,Lieschke Elizabeth,Krais John J.,Wakefield Matthew J.,Dobrovic Alexander,Bedo Justin.BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance[EB/OL].(2025-03-28)[2025-05-25].https://www.medrxiv.org/content/10.1101/2023.03.20.23287465.点此复制
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