title: BRCA2 inhibition enhances cisplatin-mediated alterations in tumor cell proliferation, metabolism, and metastasis.
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.
authors: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors: Mateusz
authors: M
authors: Rytelewski
authors: Department of Anatomy and Cell Biology, Western University, London, Ontario, Canada.
authors: Jessica G
authors: JG
authors: Tong
authors: Department of Biochemistry, Western University, London, Ontario, Canada.
authors: Adrian
authors: A
authors: Buensuceso
authors: Department of Surgery, Western University, London, Ontario, Canada.
authors: Hon S
authors: HS
authors: Leong
authors: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors: Saman
authors: S
authors: Maleki Vareki
authors: Department of Oncology, Western University, London, Ontario, Canada.
authors: Rene
authors: R
authors: Figueredo
authors: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors: Christine
authors: C
authors: Di Cresce
authors: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Sherry Y
authors: SY
authors: Wu
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Shelley M
authors: SM
authors: Herbrich
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Keith A
authors: KA
authors: Baggerly
authors: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors: Larissa
authors: L
authors: Romanow
authors: Department of Anatomy and Cell Biology, Western University, London, Ontario, Canada.
authors: Trevor
authors: T
authors: Shepherd
authors: Department of Biochemistry, Western University, London, Ontario, Canada.
authors: Bonnie J
authors: BJ
authors: Deroo
authors: 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.
authors: Anil K
authors: AK
authors: Sood
authors: Department of Oncology, Western University, London, Ontario, Canada.
authors: Ann F
authors: AF
authors: Chambers
authors: Department of Oncology, Western University, London, Ontario, Canada; Department of Pathology, Western University, London, Ontario, Canada.
authors: Mark
authors: M
authors: Vincent
authors: Department of Oncology, Western University, London, Ontario, Canada; Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada.
authors: Peter J
authors: PJ
authors: Ferguson
authors: 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.
authors: James
authors: J
authors: Koropatnick
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002642:Chick Embryo; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D009362:Neoplasm Metastasis / Q000235:genetics; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism
chemical_list: D024682:BRCA2 Protein; D020320:Oligoribonucleotides, Antisense; D051135:Rad51 Recombinase; D002945:Cisplatin
keywords: BRCA2; Cisplatin; DNA repair; Drug sensitization; metabolism; metastasis