Reference Detail

Ref Type

Journal Article

PMID

(28588062)

Authors

Kondrashova O, Nguyen M, Shield-Artin K, Tinker AV, Teng NNH, Harrell MI, Kuiper MJ, Ho GY, Barker H, Jasin M, Prakash R, Kass EM, Sullivan MR, Brunette GJ, Bernstein KA, Coleman RL, Floquet A, Friedlander M, Kichenadasse G, O'Malley DM, Oza A, Sun J, Robillard L, Maloney L, Bowtell D, Giordano H, Wakefield MJ, Kaufmann SH, Simmons AD, Harding TC, Raponi M, McNeish IA, Swisher EM, Lin KK, Scott CL, null null

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	7	9	2017 Sep	984-998	Cancer Discov

URL

Abstract Text

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 RAD51CIn 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. Cancer Discov; 7(9); 984-98. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Quigley et al., p. 999See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
RAD51C	G162Efs*9	frameshift	loss of function - predicted	RAD51C G162Efs9 indicates a shift in the reading frame starting at amino acid 162 and terminating nine residues downstream causing a premature truncation of the 376 amino acid Rad51c protein (UniProt.org). G162Efs9 has not been characterized however, due to the effects of other truncation mutations downstream of G162 (PMID: 28588062), is predicted to lead to a loss of Rad51c protein function.
RAD51C	H192_R193delinsGG	indel	no effect	RAD51C H192_R193delinsGG results in a deletion of two amino acids in the Rad51c protein combined with the insertion of two new amino acids in the same location (UniProt.org). H192_R193delinsGG, described as a reversion mutation, has no effect on Rad51c protein function, as demonstrated by restoration of homologous recombination function similar to wild-type Rad51c in cultured cells, and is associated with acquired resistance to PARP inhibitors (PMID: 28588062).	Y
RAD51C	R193*	nonsense	loss of function	RAD51C R193* results in a premature truncation of the Rad51c protein at amino acid 193 of 376 (UniProt.org). R193* confers a loss of function to the Rad51c protein as demonstrated by impairment of homologous recombination repair in cultured cells and reduced interaction with Xrcc3 and Rad51b in yeast assays (PMID: 28588062).
RAD51C	R193L	missense	no effect	RAD51C R193L does not lie within any known functional domains of the Rad51c protein (UniProt.org). R193L, described as a reversion mutation, has no effect on Rad51c protein function, as demonstrated by restoration of homologous recombination function similar to wild-type Rad51c in cultured cells, and is associated with acquired resistance to PARP inhibitors (PMID: 28588062).	Y
RAD51C	R193W	missense	no effect	RAD51C R193W does not lie within any known functional domains of the Rad51c protein (UniProt.org). R193W, described as a reversion mutation, has no effect on Rad51c protein function, as demonstrated by restoration of homologous recombination function similar to wild-type Rad51c in cultured cells, and is associated with acquired resistance to PARP inhibitors (PMID: 28588062).	Y
RAD51C	S105*	nonsense	loss of function - predicted	RAD51C S105* results in a premature truncation of the Rad51c protein at amino acid 105 of 376 (UniProt.org). S105* has not been characterized however, due to the effects of other truncation mutations downstream of S105 (PMID: 28588062), is predicted to lead to a loss of Rad51c protein function.
RAD51D	G258Sfs*50	frameshift	unknown	RAD51D G258Sfs50 indicates a shift in the reading frame starting at amino acid 258 and terminating 50 residues downstream causing a premature truncation of the 328 amino acid Rad51d protein (UniProt.org). G258Sfs50 has been identified in the scientific literature (PMID: 28588062), but has not been biochemically characterized and therefore, its effect on Rad51d protein function is unknown (PubMed, Nov 2023).
RAD51D	S257_R259delinsK	indel	no effect	RAD51D S257_R259delinsK results in a deletion of three amino acids combined with the insertion of a lysine (K) in the same location (UniProt.org). S257_R259delinsK, described as a reversion mutation, has no effect on Rad51d protein function, as demonstrated by restoration of homologous recombination function in cultured cells, and is associated with acquired resistance to PARP inhibitors (PMID: 28588062).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RAD51D G258Sfs*50	ovarian carcinoma	sensitive	Rucaparib	Preclinical - Cell culture	Actionable	In a clinical study, an ovarian carcinoma patient harboring a RAD51D G258Sfs*50 germline mutation demonstrated stable disease when treated with Rubraca (rucaparib) (PMID: 28588062).	28588062
RAD51C R193W	ovarian carcinoma	resistant	Rucaparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C R193W demonstrated resistance to Rubraca (rucaparib) in culture (PMID: 28588062).	28588062
RAD51C R193L	ovarian carcinoma	resistant	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C R193L demonstrated resistance to Lynparza (olaparib) in culture (PMID: 28588062).	28588062
RAD51C H192_R193delinsGG	ovarian carcinoma	resistant	Veliparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C H192_R193delinsGG demonstrated resistance to Veliparib (ABT-888) in culture (PMID: 28588062).	28588062
RAD51C H192_R193delinsGG	ovarian carcinoma	resistant	Rucaparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C H192_R193delinsGG demonstrated resistance to Rubraca (rucaparib) in culture (PMID: 28588062).	28588062
RAD51D S257_R259delinsK RAD51D G258Sfs*50	ovarian carcinoma	predicted - resistant	Rucaparib	Case Reports/Case Series	Actionable	In a clinical case study, an ovarian carcinoma patient harboring a RAD51D G258Sfs*50 germline mutation developed resistance to Rubraca (rucaparib) after acquisition of RAD51D S257_R259delinsK (PMID: 28588062).	28588062
RAD51C R193W	ovarian carcinoma	resistant	Niraparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C R193W demonstrated resistance to Zejula (niraparib) in culture (PMID: 28588062).	28588062
RAD51C H192_R193delinsGG	ovarian carcinoma	resistant	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C H192_R193delinsGG demonstrated resistance to Lynparza (olaparib) in culture (PMID: 28588062).	28588062
RAD51C R193L	ovarian carcinoma	resistant	Niraparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C R193L demonstrated resistance to Zejula (niraparib) in culture (PMID: 28588062).	28588062
RAD51C H192_R193delinsGG	ovarian carcinoma	resistant	Niraparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C H192_R193delinsGG demonstrated resistance to Zejula (niraparib) in culture (PMID: 28588062).	28588062
RAD51C H192_R193delinsGG	ovarian carcinoma	resistant	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C H192_R193delinsGG demonstrated resistance to Talzenna (talazoparib) in culture (PMID: 28588062).	28588062
RAD51C R193L	ovarian carcinoma	resistant	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C R193L demonstrated resistance to Talzenna (talazoparib) in culture (PMID: 28588062).	28588062
RAD51C R193*	ovarian carcinoma	predicted - sensitive	Rucaparib	Case Reports/Case Series	Actionable	In a clinical case study, an ovarian carcinoma patient harboring a RAD51C R193* germline mutation demonstrated a partial response when treated with Rubraca (rucaparib) (PMID: 28588062).	28588062
RAD51C R193W	ovarian carcinoma	resistant	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C R193W demonstrated resistance to Lynparza (olaparib) in culture (PMID: 28588062).	28588062
RAD51C R193W	ovarian carcinoma	resistant	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C R193W demonstrated resistance to Talzenna (talazoparib) in culture (PMID: 28588062).	28588062
RAD51C R193W	ovarian carcinoma	resistant	Veliparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C R193W demonstrated resistance to Veliparib (ABT-888) in culture (PMID: 28588062).	28588062
RAD51C H192_R193delinsGG RAD51C R193* RAD51C R193L RAD51C R193W	ovarian carcinoma	predicted - resistant	Rucaparib	Case Reports/Case Series	Actionable	In a clinical case study, an ovarian carcinoma patient harboring a RAD51C R193* germline mutation developed resistance to Rubraca (rucaparib) after acquisition of RAD51C R193W, RAD51C H192_R193delinsGG, and RAD51C R193L (PMID: 28588062).	28588062
RAD51C R193L	ovarian carcinoma	resistant	Rucaparib	Preclinical - Cell culture	Actionable	In a preclinical study, ovarian carcinoma cells expressing RAD51C R193L demonstrated resistance to Rubraca (rucaparib) in culture (PMID: 28588062).	28588062