Abstract 1102: Integrated genomic analysis of clear-cell ovarian cancer identifies PRKCI as a therapeutic target

Abstract

Abstract Clear-cell ovarian cancer (CCOC) is the third most common subtype of ovarian cancer. CCOC is more resistant to standard chemotherapy and has a poorer prognosis than serous and endometrioid histotypes. Through a comprehensive genomic approach, genes that are responsible for the aggressive behavior of CCOC were identified and their mechanism explored. Genome-wide DNA copy number alterations were measured in 13 CCOC cell lines using high-resolution oligonucleotide array comparative genomic hybridization (Agilent 105k Human Genome CGH Microarray). Genomic identification of significant targets in cancer (GISTIC) analysis identified 16 amplicons containing 391 genes. Integrating whole genome expression data from human CCOC tumor specimens and normal ovarian surface epithelium specimen revealed 45 amplified genes showed mRNA overexpression in CCOC tumor specimens. Among the 45 genes, protein kinase C iota (PRKCI) was amplified in 9/13 CCOC cell lines and was overexpressed (6.7 fold) in CCOC tumor specimens. Cell proliferation, migration/invasion and tumorigenicity were suppressed by knockdown of PRKCI in PRKCI-overexpressing cells (KOC-7c and OVISE) and were enhanced by overexpression of PRKCI in cells with low endogenous levels of PRKCI (ES2 and TOV21G). Targeted inhibition of PRKCI with sodium aurothiomalate (ATM) suppressed cell growth, cell migration/invasion and tumorigenicity in CCOC cells. Western blot analysis revealed that PRKCI oncogenic function was mediated through MEK/ERK and PI3K/Akt signaling pathways. Thus, PKRCI can be considered as a potential novel CCOC-specific target; not only it inhibits malignant behavior of CCOC cells, but also induces the two major molecular pathways regulating cisplatin resistance. The results from the present study indicate that our comprehensive genomic analysis of CCOC allows identification of therapeutic targets responsible for the aggressive behavior specific of this ovarian cancer histotype and thus improve its therapeutic outcome. Citation Format: Tsun Yee Tsang, Gayatry Mohapatra, Hiroaki Itamochi, Samuel C. Mok, Michael J. Birrer. Integrated genomic analysis of clear-cell ovarian cancer identifies PRKCI as a therapeutic target. [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 1102. doi:10.1158/1538-7445.AM2015-1102