Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

被引：337

作者：

Kondrashova, Olga ^{[1
,2
]}

Nguyen, Minh ^{[3
]}

Shield-Artin, Kristy ^{[1
,2
]}

Tinker, Anna V. ^{[4
]}

Teng, Nelson N. H. ^{[5
]}

Harrell, Maria I. ^{[6
]}

Kuiper, Michael J. ^{[7
]}

Ho, Gwo-Yaw ^{[1
,2
,8
]}

Barker, Holly ^{[1
,2
]}

Jasin, Maria ^{[9
]}

Prakash, Rohit ^{[9
]}

Kass, Elizabeth M. ^{[9
]}

Sullivan, Meghan R. ^{[10
]}

Brunette, Gregory J. ^{[10
]}

Bernstein, Kara A. ^{[10
]}

Coleman, Robert L. ^{[11
]}

Floquet, Anne ^{[12
]}

Friedlander, Michael ^{[13
,14
]}

Kichenadasse, Ganessan ^{[15
]}

O'Malley, David M. ^{[16
]}

Oza, Amit ^{[17
]}

Sun, James ^{[18
]}

Robillard, Liliane ^{[3
]}

Maloney, Lara ^{[3
]}

Bowtell, David ^{[19
,20
,21
,22
]}

Giordano, Heidi ^{[3
]}

Wakefield, Matthew J. ^{[1
,7
]}

Kaufmann, Scott H. ^{[23
]}

Simmons, Andrew D. ^{[3
]}

Harding, Thomas C. ^{[3
]}

Raponi, Mitch ^{[3
]}

McNeish, Iain A. ^{[24
]}

Swisher, Elizabeth M. ^{[6
]}

Lin, Kevin K. ^{[3
]}

Scott, Clare L. ^{[1
,2
,8
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, 1G Royal Parade, Melbourne, Vic, Australia

[2] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia

[3] Clovis Oncol Inc, Boulder, CO USA

[4] British Columbia Canc Agcy, Vancouver, BC, Canada

[5] Stanford Univ, Palo Alto, CA 94304 USA

[6] Univ Washington, Seattle, WA 98195 USA

[7] Univ Melbourne, Melbourne Bioinformat, Melbourne, Vic, Australia

[8] Peter MacCallum Canc Ctr, Dept Med Oncol, Melbourne, Vic, Australia

[9] Mem Sloan Kettering Canc Ctr, Dev Biol Program, 1275 York Ave, New York, NY 10021 USA

[10] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA

[11] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[12] Inst Bergonie, Bordeaux, France

[13] Univ New South Wales, Sydney, NSW, Australia

[14] Prince Wales Hosp, Sydney, NSW, Australia

[15] Flinders Univ S Australia, Adelaide, SA, Australia

[16] Ohio State Univ, James Canc Ctr, Columbus, OH 43210 USA

[17] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[18] Fdn Med Inc, Cambridge, MA USA

[19] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[20] Univ Sydney, Ctr Canc Res, Westmead Millennium Inst, Sydney, NSW, Australia

[21] Westmead Hosp, Dept Gynaecol Oncol, Sydney, NSW, Australia

[22] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

[23] Mayo Clin, Ctr Canc, Rochester, MN USA

[24] Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland

来源：

CANCER DISCOVERY | 2017年 / 7卷 / 09期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会; 美国国家卫生研究院;

关键词：

HOMOLOGOUS RECOMBINATION REPAIR; GERMLINE MUTATIONS; POLYMERASE INHIBITORS; MAINTENANCE THERAPY; MOLECULAR-DYNAMICS; PLATINUM RESPONSE; FALLOPIAN-TUBE; PHASE-2; TRIAL; DNA-DAMAGE; CANCER;

D O I：

10.1158/2159-8290.CD-17-0419

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations. SIGNIFICANCE: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. (C) 2017 AACR.

引用

页码：984 / 998

页数：15

共 47 条

[1] BRCA Mutation Frequency and Patterns of Treatment Response in BRCA Mutation-Positive Women With Ovarian Cancer: A Report From the Australian Ovarian Cancer Study Group [J].

Alsop, Kathryn ;

Fereday, Sian ;

Meldrum, Cliff ;

deFazio, Anna ;

Emmanuel, Catherine ;

George, Joshy ;

Dobrovic, Alexander ;

Birrer, Michael J. ;

Webb, Penelope M. ;

Stewart, Colin ;

Friedlander, Michael ;

Fox, Stephen ;

Bowtell, David ;

Mitchell, Gillian .

JOURNAL OF CLINICAL ONCOLOGY, 2012, 30 (21) :2654-2663

[2] An Inducible Lentiviral Guide RNA Platform Enables the Identification of Tumor-Essential Genes and Tumor-Promoting Mutations In Vivo [J].

Aubrey, Brandon J. ;

Kelly, Gemma L. ;

Kueh, Andrew J. ;

Brennan, Margs S. ;

O'Connor, Liam ;

Milla, Liz ;

Wilcox, Stephen ;

Tai, Lin ;

Strasser, Andreas ;

Herold, Marco J. .

CELL REPORTS, 2015, 10 (08) :1422-1432

[3] Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor [J].

Barber, Louise J. ;

Sandhu, Shahneen ;

Chen, Lina ;

Campbell, James ;

Kozarewa, Iwanka ;

Fenwick, Kerry ;

Assiotis, Ioannis ;

Rodrigues, Daniel Nava ;

Reis Filho, Jorge S. ;

Moreno, Victor ;

Mateo, Joaquin ;

Molife, L. Rhoda ;

De Bono, Johann ;

Kaye, Stan ;

Lord, Christopher J. ;

Ashworth, Alan .

JOURNAL OF PATHOLOGY, 2013, 229 (03) :422-429

[4] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[5] Trimmomatic: a flexible trimmer for Illumina sequence data [J].

Bolger, Anthony M. ;

Lohse, Marc ;

Usadel, Bjoern .

BIOINFORMATICS, 2014, 30 (15) :2114-2120

[6] RNA-based analysis of BRCA1 and BRCA2 gene alterations [J].

Bonatti, Fabrizia ;

Pepe, Chiara ;

Tancredi, Mariella ;

Lombardi, Grazia ;

Aretini, Paolo ;

Sensi, Elisa ;

Falaschi, Elisabetta ;

Cipollini, Giovanna ;

Bevilacqua, Generoso ;

Caligo, Maria Adelaide .

CANCER GENETICS AND CYTOGENETICS, 2006, 170 (02) :93-101

[7] Protein structure homology modeling using SWISS-MODEL workspace [J].

Bordoli, Lorenza ;

Kiefer, Florian ;

Arnold, Konstantin ;

Benkert, Pascal ;

Battey, James ;

Schwede, Torsten .

NATURE PROTOCOLS, 2009, 4 (01) :1-13

[8] Crystal structure of a Rad51 filament [J].

Conway, AB ;

Lynch, TW ;

Zhang, Y ;

Fortin, GS ;

Fung, CW ;

Symington, LS ;

Rice, PA .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2004, 11 (08) :791-796

[9] DNA repair dysregulation from cancer driver to therapeutic target [J].

Curtin, Nicola J. .

NATURE REVIEWS CANCER, 2012, 12 (12) :801-817

[10] Resistance to therapy caused by intragenic deletion in BRCA2 [J].

Edwards, Stacey L. ;

Brough, Rachel ;

Lord, Christopher J. ;

Natrajan, Rachael ;

Vatcheva, Radost ;

Levine, Douglas A. ;

Boyd, Jeff ;

Reis-Filho, Jorge S. ;

Ashworth, Alan .

NATURE, 2008, 451 (7182) :1111-U8

← 1 2 3 4 5 →