<i>BRCA</i> Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

Lin, Kevin K.; Harrell, Maria I.; Oza, Amit M.; Oaknin, Ana; Ray‐Coquard, Isabelle; Tinker, Anna V.; Helman, Elena; Radke, Marc R.; Say, Carmen; Vo, Lan Thanh; Mann, Elaina; Isaacson, Jeffrey D.; Maloney, Lara; O’Malley, David M.; Chambers, Setsuko K.; Kaufmann, Scott H.; Scott, Clare L.; Konecny, Gottfried E.; Coleman, Robert L.; Sun, James; Giordano, Heidi; Brenton, James D.; Harding, Thomas C.; McNeish, Iain A.; Swisher, Elizabeth M.

doi:10.1158/2159-8290.cd-18-0715

Cited by 322 publications

(269 citation statements)

References 30 publications

(46 reference statements)

Supporting

Mentioning

256

Contrasting

Unclassified

Order By: Relevance

“…The first example of PARP inhibitor resistance was identified in Capan-1 cells derived from a pancreatic epithelial tumour, which had an intragenic deletion in BRCA2 of 458 bp resulting in removal of the inactivating frameshift mutation and expression of an almost full-length BRCA2 protein lacking 153 amino acids (Edwards et al 2008). Since then, many examples of secondary mutations in BRCA1/2, as well as RAD51C, RAD51D, and PALB2, that genetically revert the mutation and restore functional full-length protein have been reported in breast, ovarian, pancreatic, and prostate carcinoma (Sakai et al 2008;Norquist et al 2011;Barber et al 2013;Patch et al 2015;Christie et al 2017;Goodall et al 2017;Kondrashova et al 2017;Lheureux et al 2017a;Pishvaian et al 2017;Quigley et al 2017;Weigelt et al 2017;Lin et al 2019). Platinum and cisplatin chemotherapy seem to select for these secondary mutation events (Sakai et al 2008;Norquist et al 2011).…”

Section: Restoration Of the Hr Pathwaymentioning

confidence: 99%

PARP and PARG inhibitors in cancer treatment

2020

View full text Add to dashboard Cite

Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.

show abstract

Section: Restoration Of the Hr Pathwaymentioning

confidence: 99%

PARP and PARG inhibitors in cancer treatment

2020

View full text Add to dashboard Cite

show abstract

“…This will allow much-needed large cohort studies on resistance mechanisms in patients ( Figure 2). Even though numbers are limited to date, studies have already shown that reversion mutations in BRCA1 and BRCA2 occur frequently in PARPi-resistant cancers [43,45,50,51,53,94,95]. In studies on PDX models of BRCA1-mutated tumors, concomitant loss of TP53BP1 or REV7 was identified in up to 20% of the resistant tumors [96,97].…”

Section: Resistance Mechanisms In the Clinicmentioning

confidence: 99%

PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells

Noordermeer

Attikum

2019

Trends in Cell Biology

344

285

View full text Add to dashboard Cite

Poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with deficiency for homologous recombination (HR), a pathway essential for DNA double-strand break repair. PARP inhibitors (PARPi) therefore hold great promise for the treatment of tumors with disruptive mutations in BRCA1/2 or other HR factors. Unfortunately, PARPi resistance has proved to be a major problem in the clinic. Knowledge about PARPi resistance is expanding quickly, revealing four main mechanisms that alter drug availability, affect (de)PARylation enzymes, restore HR, or restore replication fork stability. We discuss how studies on resistance mechanisms have yielded important insights into the regulation of DNA double-strand break (DSB) repair and replication fork protection, and how these studies could pave the way for novel treatment options to target resistance mechanisms or acquired vulnerabilities. Defective DSB Repair and Cancer Genomic instability is one of the enabling characteristics of tumor development [1]. To maintain genomic integrity, cells are equipped with multiple mechanisms to repair a wide variety of DNA lesions caused by exogenous and endogenous events. One particularly toxic lesion is the DNA double-strand break (DSB; see Glossary). This lesion can be caused by ionizing irradiation and genotoxic chemicals, but can also arise as an intermediate of resolving stalled or collapsed replication forks (replication fork instability) [2]. If left unrepaired or are repaired incorrectly, DSBs can give rise to mutations, deletions, amplifications, and chromosomal translocations, leading to various outcomes such as senescence, cell death, or malignant transformation. Over 30 years ago, Marie-Claire King and colleagues discovered the linkage between familial earlyonset breast cancer and the genomic region 17q21 [3]. We now know that the gene affected is BRCA1, and that mutations in this gene are not only linked to breast cancer but also to familial cases of ovarian cancer and sporadic tumors of different origins [4-7]. BRCA1 is an essential factor in the repair of DSBs via homologous recombination (HR) (see Box 1 for a more detailed overview of DSB repair). Moreover, homozygous loss of BRCA1 is not tolerated during human and mouse embryonic development [8]. This BRCA1 survival-dependency can be partially overcome by concomitant loss of p53 [9]. Importantly, mouse models with mammary gland-specific loss of these genes show increased breast tumor formation [8]. Indeed, in clinical tumor samples, BRCA1 mutations often co-occurbut not alwayswith TP53 mutations [8,10]. Epigenetic silencing of BRCA1 expression via promoter hypermethylation is another way of reducing BRCA1 activity, and this has been shown to occur frequently in tumors [6,11,12]. In addition to aberrations in BRCA1, genes encoding many more factors involved in HR, such as BRCA2, PALB2, and RAD51, are known to be affected in a wide variety of tumors. All these tumors display severe chromosomal instability as a result of deregulated HR, a phenotype referred to as 'BRCAne...

show abstract

“…PARP inhibitors have been approved for the treatment of BRCA1/2 mutant ovarian and breast cancers. A key mechanism of resistance to PARP inhibitors and platinum-based chemotherapy in these cancers is the acquisition of reversion mutations in BRCA1/2 that restore protein function [3,4]. Reversion mutations in BRCA2 have also been observed in a small number of mCRPC patients treated with PARP inhibitors or carboplatin [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…Acquired reversion mutations in BRCA1/2 resulting from exposure to platinum chemotherapy are likely to render tumors less sensitive to PARP inhibitor treatment. In a recent study of patients with ovarian cancer treated with rucaparib following platinum, patients without BRCA1/2 reversion mutations had a significantly longer median progression-free survival than patients with reversion mutations (9.0 vs. 1.8 months; hazard ratio, 0.12; P < 0.0001) [3]. However, there are limited data on the combination or sequential use of platinum and PARP inhibitors in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Polyclonal BRCA2 mutations following carboplatin treatment confer resistance to the PARP inhibitor rucaparib in a patient with mCRPC: a case report

2020

View full text Add to dashboard Cite

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for the treatment of breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutant ovarian and breast cancers, and are now being evaluated in metastatic castration-resistant prostate cancer (mCRPC). Reversion mutations that restore BRCA1/2 function have been shown to be responsible for resistance to platinum-based chemotherapy and PARP inhibitors, however there is no information on the sequential use of these agents in prostate cancer. Case presentation: A patient with mCRPC associated with a germline BRCA2 mutation was sequentially treated with carboplatin and the PARP inhibitor rucaparib. Genomic profiling of the available baseline tumor and progression blood samples using next-generation sequencing panel tests identified polyclonal BRCA2 reversion mutations post carboplatin treatment but prior to rucaparib treatment. A total of 12 somatic reversion mutations were detected and ranged from small indels to larger deletions of up to 387 amino acids. These alterations are all predicted to restore the BRCA2 open reading frame and potentially protein function. The patient received limited benefit while on rucaparib, likely due to these reversion mutations observed prior to treatment. Conclusions: Here we report a case of a patient with prostate cancer who received a platinum agent and PARP inhibitor sequentially and in whom polyclonal BRCA2 reversion mutations were identified as the likely mechanism of acquired resistance to carboplatin and primary resistance to PARP inhibition. These findings suggest caution is warranted in sequencing these agents.

show abstract

BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

Cited by 322 publications

References 30 publications

PARP and PARG inhibitors in cancer treatment

PARP and PARG inhibitors in cancer treatment

PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells

Polyclonal BRCA2 mutations following carboplatin treatment confer resistance to the PARP inhibitor rucaparib in a patient with mCRPC: a case report

Contact Info

Product

Resources

About