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.