Abstract C77: A novel BRCA2 targeting antisense oligonucleotide sensitizes human tumor cells to chemotherapy and radiotherapy - the induction of ‘complementary lethality’ by targeting DNA repair.

Abstract

Abstract BRCA2 is a protein involved in homologous recombination repair of double-stranded DNA breaks in human cells. Inactivating mutations in BRCA2 predispose to early onset cancer of the breast, ovary and other tissues. However, patients with tumors that harbour BRCA2 mutations respond more favourably to cancer therapy. Therefore, inhibiting BRCA2 function in cancer cells capable of homologous recombination repair may sensitize otherwise resistant tumors to distinct types of anti-cancer treatment. We have reported that BRCA2 siRNA sensitizes human tumor cells to specific DNA-damaging agents (e.g., cisplatin), but not anti-folate drugs (e.g., pemetrexed), a phenomenon we termed ‘complementary lethality’. Based on these results, we developed and are testing a second generation antisense oligodeoxynucleotide (BR-1) that specifically targets BRCA2. BR-1 decreased BRCA2 mRNA and protein levels, and also inhibited BRCA2-mediated RAD51 repair focus formation. BR-1 potently sensitized human non-small cell lung cancer (A549) cells to cisplatin, melphalan, and carboplatin as evidenced by reduced overall proliferation. In addition, A549 cells exhibited reduced ability to form colonies after concomitant treatment with BR-1 and cisplatin, melphalan, or ionizing radiation. Furthermore, cisplatin-resistant, patient-derived head and neck squamous cancer cells (HN-5a) were rendered sensitive to cisplatin following BR-1 treatment, and the level of cisplatin sensitivity was comparable to that of the parent population. Interestingly, treatment with BR-1 and cisplatin significantly decreased cellular respiration compared to control oligonucleotide and cisplatin treatment, suggesting that downregulation of BRCA2 in the context of alkylating drug treatment alters cellular metabolism. However, this change in respiration occurred independently of mitochondrial integrity. BR-1 is currently being tested in vivo to determine its ability to downregulate BRCA2 in human xenografts and sensitize solid tumors to chemotherapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C77. Citation Format: Mateusz Rytelewski, Jessica Tong, Adrian Buensucesco, Saman Maleki Vareki, Peter J. Ferguson, Rene Figueredo, Mark Vincent, Trevor Shepherd, Bonnie J. Deroo, James D. Koropatnick. A novel BRCA2 targeting antisense oligonucleotide sensitizes human tumor cells to chemotherapy and radiotherapy - the induction of ‘complementary lethality’ by targeting DNA repair. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C77.