Role of protein kinase ADCK5 in ovarian cancer

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Project Summary: Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause for cancer-related deaths among women in the United States. Due to the absence of reliable early biomarkers, more than 85% patients are diagnosed with metastatic disease that are resistant to extant chemotherapeutics. Consequently, the 5-year survival rate for these patients is extremely poor (<30%). This disappointing clinical reality underscores the urgent need to address existing knowledge gaps in our understanding of factors that drives ovarian cancer progression and identify new therapeutic targets that will help overcome the limitations of extant strategies. Our compelling preliminary data suggests that the atypical serine-threonine protein kinase, AarF domain containing kinase 5 (ADCK5) plays a key role in ovarian cancer progression and drug response. The genomic locus harboring ADCK5, 8q24.3, is amplified frequently in ovarian cancer and ADCK5 is overexpressed in about 37 percent ovarian cancers. Clinical data reveal that ADCK5 overexpression significantly decreased survival in ovarian cancer patients with p53 mutant tumors. Importantly, p53 mutations are observed in over 96% of high- grade serous ovarian carcinomas. In contrast, ADCK5 overexpression did not have any impact on patients with wild type (WT) p53 tumors. Consistently, ADCK5 overexpression promoted proliferation, migration, invasion, and attachment to extracellular matrix proteins in mutant p53 expressing ovarian cancer cell lines but not WT-p53 expressing cell lines. Interestingly, ADCK5 overexpression in mutant p53, but not WT-p53, expressing cell lines resulted in increased resistance to the chemotherapeutic agents such as carboplatin and doxorubicin. Despite these exciting data, no report till date has investigated ADCK5’s role in ovarian cancer or its utility as a therapeutic target. In this proposal we will address this critical knowledge gap. In Aim 1, we will determine ADCK5’s role in ovarian cancer progression and metastasis. Patient-derived and engineered ovarian cancer cell lines and clinically relevant in vivo models will be used to characterize the functional interaction between tumor p53-status and ADCK5 in ovarian cancer. Transcriptomic and proteomic approaches will be employed to determine biological processes and molecular pathways that drive ADCK5 mediated ovarian cancer progression and drug resistance. Aim 2 will determine the ADCK5’s utility as a therapeutic target in mutant p53 expressing ovarian tumors using clinically relevant in vitro and in vivo models. These studies will therefore establish role for ADCK5, a largely unknown but important protein kinase, in ovarian cancer. Given that ADCK5 is overexpressed in several human malignancies (lung, pancreatic, liver, bladder etc.) and p53 mutations are observed in over 50% of all human cancers, the impact of the proposed work will extend well beyond ovarian cancer.