TY - JOUR
T1 - Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma
AU - AOCS Study Group
AU - Kondrashova, Olga
AU - Nguyen, Minh
AU - Shield-Artin, Kristy
AU - Tinker, Anna V.
AU - Teng, Nelson N.H.
AU - Harrell, Maria I.
AU - Kuiper, Michael J.
AU - Ho, Gwo Yaw
AU - Barker, Holly
AU - Jasin, Maria
AU - Prakash, Rohit
AU - Kass, Elizabeth M.
AU - Sullivan, Meghan R.
AU - Brunette, Gregory J.
AU - Bernstein, Kara A.
AU - Coleman, Robert L.
AU - Floquet, Anne
AU - Friedlander, Michael
AU - Kichenadasse, Ganessan
AU - O’Malley, David M.
AU - Oza, Amit
AU - Sun, James
AU - Robillard, Liliane
AU - Maloney, Lara
AU - Bowtell, David
AU - Giordano, Heidi
AU - Wakefield, Matthew J.
AU - Kaufmann, Scott H.
AU - Simmons, Andrew D.
AU - Harding, Thomas C.
AU - Raponi, Mitch
AU - McNeish, Iain A.
AU - Swisher, Elizabeth M.
AU - Lin, Kevin K.
AU - Scott, Clare L.
PY - 2017/9
Y1 - 2017/9
N2 - 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.
AB - 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.
KW - Ovarian Carcinoma
KW - BRCA1
KW - BRCA2
UR - http://www.scopus.com/inward/record.url?scp=85028769539&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1062702
UR - http://purl.org/au-research/grants/NHMRC/400413
UR - http://purl.org/au-research/grants/NHMRC/400281
U2 - 10.1158/2159-8290.CD-17-0419
DO - 10.1158/2159-8290.CD-17-0419
M3 - Article
C2 - 28588062
AN - SCOPUS:85028769539
SN - 2159-8274
VL - 7
SP - 984
EP - 998
JO - Cancer Discovery
JF - Cancer Discovery
IS - 9
ER -