Interrogating MRCK Protein Kinases in Ovarian Cancer

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as “NOT-CA- 24-044. Uterine serous carcinoma (USC) is the deadliest form of endometrial cancer that currently lacks effective targeted therapies. Moreover, Black women are twice as likely to die from USC than White women in the United

States, consequently, the molecular features that contribute to this disparity are avidly being investigated. Importantly, USC and high-grade serous ovarian carcinomas (HGSOC) share similar molecular features, clinical properties, and treatments, suggesting that molecular targeted therapies in HGSOC may be relevant to USC. In

our R01 (CA282766), we are actively exploring the MRCK protein kinases as drug targets for the treatment of recurrent HGSOC. The overall goal of this administrative supplement is to determine whether MRCKs represent a therapeutic target in USC, and whether differences in protein kinase activity exists amongst USC tumors

isolated from Black or White women that could contribute to the disparity. Our preliminary studies showed that inhibition of MRCKs impaired actin cytoskeleton remodeling blocking spheroid invasion of USC cells, suggesting MRCKs may have therapeutic potential in USC. Moreover, preliminary proteomics assessment of kinase activity

in USC tumors showed that several kinases were elevated that have clinical drugs readily available. Nevertheless, the mechanistic basis for MRCK support of USC pathogenesis and whether USC tumors isolated from Black or White women exhibit distinct kinase activation profiles that can be targeted clinically remains poorly

understood. Our overall hypothesis is that MRCKs control spheroid growth and invasion of USC cells and that USC tumors isolated from Black or White women will exhibit distinct kinase activity signatures that contributes to disparity in USC incidence. To test this hypothesis, we have designed two Specific Aims, Aim1: Determine

the effect of MRCK inhibition on USC signaling, spheroid growth and invasion and Aim2: Define the kinome activation signature of USC tumors isolated from Black or White women to rationally predict kinase inhibitor therapies and to explore racial disparity. In Aim1, we will block MRCK function by genetic ablation or inhibitors

and monitor viability, invasion and actin remodeling of USC spheroids. In Aim 2, we will use proteomics methods to measure kinase activity in USC tumors and normal endometrium tissues isolated from Black or White women. We will then use bioinformatics and biostatistics to identify upregulated kinases in USC tumors, as well as

differences in kinase activity amongst USC tumors isolated from Black or White women. Together, the work proposed here will identify new kinase targets for the treatment of USC and explore the role of kinase signaling in the disparity of USC amongst Black and White women. Importantly, these findings will be directly relevant to

HGSOC, which can be integrated into our ongoing R01 (CA282766) HGSOC studies.