Abstract 5466: Integrative TCGA analyses identify Basonuclin1 (BNC1) as a key mediator for platinum resistance

Abstract

Abstract Objective. We have previously shown that platinum-resistant (disease progression within 6 months of diagnosis) high-grade serous ovarian cancer (HGSOC) expresses higher levels of basonuclin1 (BNC1) compared to platinum-sensitive tumors (no disease progression for more than 2 years). Here, we aim to systematically examine the functional effects of BNC1 silencing on tumor sensitivity to platinum and other commonly used chemotherapeutic agents in multiple cancer models. Methods. An integrative analysis was performed using The Cancer Genome Atlas (TCGA) dataset to systematically identify genes associated with platinum-resistance in patients with HGSOC. The biological effects of BNC1, one of the lead candidates identified, were studied in HGSOC (HeyA8-MDR, PEO4), endometrioid ovarian (A2780-CP20), clear cell ovarian (ES2), and squamous cell lung (H1299) cancer models both in vitro and in vivo. The effects of BNC1 silencing or overexpression on the sensitivity of cancer cells to paclitaxel, gemcitabine, doxorubicin, and cisplatin treatments were assessed. Results. BNC1 expression was increased by more than two-fold in platinum-resistant tumors in the TCGA ovarian cancer dataset. BNC1 silencing increased the sensitivity of A2780-CP20, HeyA8-MDR, PEO4, ES2, and H1299 cells to cisplatin and doxorubicin treatments, but not to gemcitabine or taxane-based therapies. BNC1-silenced cells showed a 3-fold average increase in the percentage of apoptotic cells following cisplatin treatment, when compared to cells treated with control siRNA. Importantly, combination treatment of siBNC1 and cisplatin resulted in a 90% reduction in tumor burden in platinum-resistant A2780-CP20 and HeyA8-MDR orthotopic ovarian cancer mouse models when compared to control siRNA plus cisplatin treatment group. Overexpression of BNC1 in platinum-sensitive A2780 cells led to a 2.5-fold reduction in cisplatin sensitivity in vivo as measured by total tumor burden 4 weeks after therapy. Conclusion. Collectively, BNC1 represents an important target for enhancing platinum-sensitivity in ovarian and lung cancer. Targeting BNC1 in platinum-resistant malignancies may improve patient survival. Note: This abstract was not presented at the meeting. Citation Format: Sherry Y. Wu, Justyna Filant, Michael McGuire, Rajesha Rupaimoole, Sunila Pradeep, Anna Unruh, Herbrich Shelley, Cristina Ivan, Ruder Dennis, Cristian Rodriguez-Aguayo, Vasudha Sehgal, Takahito Miyake, Archana Nagaraja, Kshipra Gharpure, Guillermo Armaiz, Rebecca Previs, Gabriel Lopez-Berestein, Prahlad Ram, Keith Baggerly, Anil Sood. Integrative TCGA analyses identify Basonuclin1 (BNC1) as a key mediator for platinum resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5466. doi:10.1158/1538-7445.AM2015-5466