Abstract
Targeted therapies have been used to combat many tumor types; however, few have effectively improved the overall survival in women with epithelial ovarian cancer, begging for a better understanding of this deadly disease and identification of essential drivers of tumorigenesis that can be targeted effectively. Therefore, we used a loss-of-function screening approach to help identify molecular vulnerabilities that may represent key points of therapeutic intervention. We employed an unbiased high-throughput lethality screen using a 24,088 siRNA library targeting over 6,000 druggable genes and studied their effects on growth and/or survival of epithelial ovarian cancer (EOC) cell lines. The top 300 “hits” affecting the viability of A1847 cells were rescreened across additional EOC cell lines and non-tumorigenic, human immortalized ovarian epithelial cell lines. Fifty-three gene candidates were found to exhibit effects in all tumorigenic cell lines tested. Extensive validation of these hits refined the list to four high quality candidates (HSPA5, NDC80, NUF2, and PTN). Mechanistic studies show that silencing of three genes leads to increased apoptosis, while HSPA5 silencing appears to alter cell growth through G1 cell cycle arrest. Furthermore, two independent gene expression studies show that NDC80, NUF2 and PTN were significantly aberrantly overexpressed in serous adenocarcinomas. Overall, our functional genomics results integrated with the genomics data provide an important unbiased avenue towards the identification of prospective therapeutic targets for drug discovery, which is an urgent and unmet clinical need for ovarian cancer.
Highlights
IntroductionEpithelial ovarian cancer is the second most common gynecological cancer, and one of the deadliest, among women, with an estimated 22,280 new cases and 15,500 deaths for 2012. [1] Among the different types of epithelial ovarian cancer, which includes serous, mucinous, clear cell and endometrial [2,3], the majority of deaths from ovarian cancer occur in patients with advanced-stage, high-grade serous ovarian cancer. [4] As such, there is an urgent need for new therapeutic approaches to combat this deadly disease.Development of new therapies, especially in the era of targeted treatments and personalized medicine, is typically driven by understanding the underlying biology, molecular biology and biochemistry of tumor cells and their surrounding microenvironments targeting genetic alterations. [5] This is a common theme in drug discovery and can provide specificity, but cannot generally provide comprehensiveness in targeting
Using an integrated RNAi screening approach to target over 6,000 druggable genes we identified 53 that were required for growth and survival across a panel of epithelial ovarian cancer (EOC) cell lines; seven of these were predominantly active in tumorigenic cells and were considered for additional deconvolution and validation studies
The loss-of-function screening studies reported in this paper have provided us with a functional genomic snapshot of novel molecular vulnerabilities in epithelial ovarian cancer outside the realm of commonly targeted molecular signaling pathways
Summary
Epithelial ovarian cancer is the second most common gynecological cancer, and one of the deadliest, among women, with an estimated 22,280 new cases and 15,500 deaths for 2012. [1] Among the different types of epithelial ovarian cancer, which includes serous, mucinous, clear cell and endometrial [2,3], the majority of deaths from ovarian cancer occur in patients with advanced-stage, high-grade serous ovarian cancer. [4] As such, there is an urgent need for new therapeutic approaches to combat this deadly disease.Development of new therapies, especially in the era of targeted treatments and personalized medicine, is typically driven by understanding the underlying biology, molecular biology and biochemistry of tumor cells and their surrounding microenvironments targeting genetic alterations. [5] This is a common theme in drug discovery and can provide specificity, but cannot generally provide comprehensiveness in targeting. Epithelial ovarian cancer is the second most common gynecological cancer, and one of the deadliest, among women, with an estimated 22,280 new cases and 15,500 deaths for 2012. Development of new therapies, especially in the era of targeted treatments and personalized medicine, is typically driven by understanding the underlying biology, molecular biology and biochemistry of tumor cells and their surrounding microenvironments targeting genetic alterations. Cancer cells can evolve that lack the targeted genetic alterations or that are resistant and could cause progressive disease. The evolutionary nature of cancer implies, contrary to conventional wisdom, that the essential features of any therapy for the consistent cure or control of cancer must be independent of the particular pathways of tumor cell evolution, and independent of any particular genetic or epigenetic alterations. We found NDC80, NUF2 and PTN as important molecular vulnerabilities, which represent potentially important therapeutic targets in ovarian cancer
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