Targeting DNA Repair in Cancer: Beyond PARP Inhibitors

Brown, Jessica; O’Carrigan, Brent; Jackson, Stephen; Yap, Timothy A.

doi:10.1158/2159-8290.cd-16-0860

Cited by 502 publications

(495 citation statements)

References 166 publications

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“…Tumor DNA from ovarian cancer patients, cfDNA from ovarian and breast cancer patients and their respective germline DNA were subjected to targeted massively parallel sequencing in the MSKCC Integrated Genomics Operation (IGO) as previously described (24,25) using a custom panel of baits encompassing all exons and introns of BRCA1 and BRCA2 , and all exons of 141 additional genes reported to be involved in DNA repair, drug resistance, resistance to PARP-inhibitors/ platinum-salts, and genes recurrently mutated in ovarian cancer, including TP53 (Supplementary Table S1) (26–28). In addition, baits tiling common single nucleotide polymorphisms (SNPs) were included to allow for copy number analysis (25).…”

Section: Methodsmentioning

confidence: 99%

Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

Weigelt

Comino-Méndez

Bruijn

et al. 2017

Clinical Cancer Research

211

129

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Purpose Resistance to platinum-based chemotherapy or PARP inhibition in germline BRCA1 or BRCA2 mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether BRCA1/2 reversion mutations could be identified in circulating cell-free DNA (cfDNA) of ovarian or breast cancer patients previously treated with platinum and/or PARP inhibitors. Experimental Design cfDNA from 24 prospectively accrued BRCA1- or BRCA2-germline mutant patients, including 19 platinum-resistant/refractory ovarian cancer and five platinum and/or PARP inhibitor pre-treated metastatic breast cancer patients, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of BRCA1 and BRCA2. Functional studies were performed to assess the impact of the putative BRCA1/2 reversion mutations on BRCA1/2 function. Results Diverse and often polyclonal putative BRCA1 or BRCA2 reversion mutations were identified in cfDNA from four ovarian cancer patients (21%) and from two breast cancer patients (40%). BRCA2 reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a breast cancer patient who did not respond to treatment, and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function. Conclusions Putative BRCA1/2 reversion mutations can be detected by cfDNA sequencing analysis in ovarian and breast cancer patients. Our findings warrant further investigation of cfDNA sequencing to identify putative BRCA1/2 reversion mutations and to aid the selection of patients for PARP inhibition therapy.

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Section: Methodsmentioning

confidence: 99%

Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

Weigelt

Comino-Méndez

Bruijn

et al. 2017

Clinical Cancer Research

211

129

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“…The DDR pathway as a therapeutic target and opportunity for hematopoietic malignancies Besides favoring tumor formation and progression, DDR defects can provide a therapeutic opportunity, since cancer cells with a reduced ability to repair DNA lesions can acquire hypersensitivity to chemotherapeutic drugs that directly damage the DNA or act through synthetic lethal interactions [27,28].…”

Section: The Essential Function Of Ddr In the Maintenance Of Hscsmentioning

confidence: 99%

The DNA damage response pathway in normal hematopoiesis and malignancies

Delia

Mizutani

2017

Int J Hematol

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“…[24–27] Small molecule inhibitors of numerous other DNA repair proteins – many of them kinases involved in DNA damage response pathways (such as ATM, ATR, CHEK1, CHEK2, WEE1, and DNA-PKcs) – are now being tested in a variety of DNA repair-deficient and DNA repair-proficient tumor settings as single agents and in combinations with conventional DNA damaging agents. [28–30]…”

Section: Introductionmentioning

confidence: 99%

DNA Damage and Repair Biomarkers of Immunotherapy Response

et al. 2017

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DNA damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the anti-tumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.

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Targeting DNA Repair in Cancer: Beyond PARP Inhibitors

Cited by 502 publications

References 166 publications

Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

The DNA damage response pathway in normal hematopoiesis and malignancies

DNA Damage and Repair Biomarkers of Immunotherapy Response

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