Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors.
David A. Quigley,Joshi J. Alumkal,Alexander W. Wyatt,Vishal Kothari,Adam Foye,Paul Lloyd,Rahul Aggarwal,Won Kim,Eric Lu,Jacob Schwartzman,Kevin Beja,Matti Annala,Rajdeep Das,Morgan E. Diolaiti,Colin C. Pritchard,George Thomas,Scott A. Tomlins,Karen E. Knudsen,Christopher J. Lord,Charles J. Ryan,Jack F. Youngren,Tomasz M. Beer,Alan Ashworth,Eric J. Small,Felix Y. Feng +24 more
TLDR
BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib are identified and it is shown that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PAR Pi resistance.Abstract:
Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2 HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.Significance: The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999-1005. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.read more
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Olaparib in hormone receptor-positive, HER2-negative metastatic breast cancer with a somatic BRCA2 mutation.
TL;DR: The oral poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib is approved for the treatment of patients with human epidermal growth factor 2-negative (HER2−) metastatic breast cancer (m...
Journal ArticleDOI
Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition
Arafat Siddiqui,Manuela Tumiati,Alia Joko,Jouko Sandholm,Pia Roering,Sofia Aakko,Reetta Vainionpää,Katja Kaipio,Kaisa Huhtinen,Liisa Kauppi,Johanna Tuomela,Sakari Hietanen +11 more
TL;DR: In this article, the authors used a low-dose topoisomerase II inhibitor mitoxantrone to induce DNA damage which caused a transient cell cycle delay but allowed eventual passage through this checkpoint in most cells.
Journal ArticleDOI
Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers
TL;DR: In this paper , the authors performed multi-omic sequencing on 67 paired primary and recurrent BrCa and OvCa from 27 BRCA1/2 mutation carriers to identify potential recurrence-specific drivers.
Journal ArticleDOI
Pre-Existing and Acquired Resistance to PARP Inhibitor-Induced Synthetic Lethality
TL;DR: In this paper , a review of the existing and acquired resistance to PARP inhibitors and potential therapeutic solutions is presented, and the potential rationales for developing effective therapies to prevent/repress the PARPi resistance in cancer cells are discussed.
Journal ArticleDOI
Current and future landscape of poly (ADP-ribose) polymerase inhibition resistance.
TL;DR: There is increasing clinical interest to identify options to enhance PARPi efficacy and overcome adaptive resistance, and relevant strategies to overcome poly(ADP-ribose) polymerase (PARP) inhibitor resistance are highlighted.
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