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Mol Oncol. 2014 Dec;8(8):1429-40. doi: 10.1016/j.molonc.2014.05.017. Epub 2014 Jun 6.

BRCA2 inhibition enhances cisplatin-mediated alterations in tumor cell proliferation, metabolism, and metastasis.

Author information

1
Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
2
Department of Anatomy and Cell Biology, Western University, London, Ontario, Canada.
3
Department of Biochemistry, Western University, London, Ontario, Canada.
4
Department of Surgery, Western University, London, Ontario, Canada.
5
Department of Oncology, Western University, London, Ontario, Canada.
6
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
9
Department of Oncology, Western University, London, Ontario, Canada; Department of Pathology, Western University, London, Ontario, Canada.
10
Department of Oncology, Western University, London, Ontario, Canada; Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada.
11
Department of Microbiology and Immunology, Western University, London, Ontario, Canada; Department of Oncology, Western University, London, Ontario, Canada; Department of Pathology, Western University, London, Ontario, Canada; Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada. Electronic address: jkoropat@uwo.ca.

Abstract

Tumor cells have unstable genomes relative to non-tumor cells. Decreased DNA integrity resulting from tumor cell instability is important in generating favorable therapeutic indices, and intact DNA repair mediates resistance to therapy. Targeting DNA repair to promote the action of anti-cancer agents is therefore an attractive therapeutic strategy. BRCA2 is involved in homologous recombination repair. BRCA2 defects increase cancer risk but, paradoxically, cancer patients with BRCA2 mutations have better survival rates. We queried TCGA data and found that BRCA2 alterations led to increased survival in patients with ovarian and endometrial cancer. We developed a BRCA2-targeting second-generation antisense oligonucleotide (ASO), which sensitized human lung, ovarian, and breast cancer cells to cisplatin by as much as 60%. BRCA2 ASO treatment overcame acquired cisplatin resistance in head and neck cancer cells, but induced minimal cisplatin sensitivity in non-tumor cells. BRCA2 ASO plus cisplatin reduced respiration as an early event preceding cell death, concurrent with increased glucose uptake without a difference in glycolysis. BRCA2 ASO and cisplatin decreased metastatic frequency in vivo by 77%. These results implicate BRCA2 as a regulator of metastatic frequency and cellular metabolic response following cisplatin treatment. BRCA2 ASO, in combination with cisplatin, is a potential therapeutic anti-cancer agent.

KEYWORDS:

BRCA2; Cisplatin; DNA repair; Drug sensitization; metabolism; metastasis

PMID:
24974076
PMCID:
PMC5528603
DOI:
10.1016/j.molonc.2014.05.017
[Indexed for MEDLINE]
Free PMC Article

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