PHILADELPHIA (February 18, 2020) – In a study published today, researchers at Fox Chase Cancer Center have identified a new kinase target for the treatment of high-grade serous ovarian cancer that has the potential to lead to the development of new drugs.
James S. Duncan, PhD, an assistant professor in the Cancer Biology Program at Fox Chase, and colleagues, discovered that the MRCKA kinase plays an integral role in ovarian cancer cell migration, proliferation, and survival.
“There are very few effective targeted therapies for high-grade serous ovarian cancer,” Duncan said. “PARP inhibitors have been shown to be effective in some ovarian cancers, but as far as targeting kinases, there haven’t been any home runs.”
Kinases help control many important functions of the cell such as cell signaling, metabolism, division, and survival. Kinase inhibitors have been used successfully in other types of cancer to block cell growth or the growth of new blood vessels needed for tumor growth. Some of the most well-known kinase inhibitors, for example, are those designed to block the Bcr-Abl fusion gene in leukemia.
In their study, Duncan and colleagues used a unique proteomic technology that allowed them to map the entire landscape of the kinome, the sum of all protein kinases in the cell. “First, we looked at tumors from patients and patient-derived xenograft models to see if any of these unknown kinases were highly expressed,” Duncan said.
This process identified several established ovarian cancer driver kinases, as well as several more that have not been previously explored. “Then we did loss-of-function studies to inhibit these kinases in order to ask if their inhibition had any impact on ovarian cancer cell growth and survival,” Duncan added.
These studies identified MRCKA as a possible therapeutic target. Next, the researchers inhibited MRCKA in ovarian cancer cell lines and found that this kinase regulated many key processes in ovarian cancer cells.
“We identified a kinase that we think is essential for many ovarian cancer cell survival processes,” Duncan said. “A small molecule has been developed and we demonstrated that inhibition of MRCKA can have an effect on killing ovarian cancer cells.”
Additionally, one of the issues occurring in women with ovarian cancer is the formation of spheroids, or clusters of tumor cells, which represent a major component of resistance to chemotherapy and recurrent disease. Using the small molecule to inhibit MRCKA blocked cell growth and spheroid formation in ovarian cancer cells lines.
“This means MRCKA shows strong therapeutic potential because it is involved in this kind of spheroid development, which is one of the key things driving resistance to a lot of drugs,” Duncan said. “Together, this opens the avenue that this kinase could be a very essential kinase for ovarian cancer therapy.”
This work was supported by grants from the National Institutes CORE Grant CA06927, R01 CA211670, R01 CA142928, a grant from the Pennsylvania Department of Health (SAP#4100068716), NIH T32 CA009035, Fox Chase Cancer Center Interdisciplinary Translational Cancer Research Grants, and American Cancer Society IRG-92-027-20. Support was also provided by generous donations from the Teal Tea Foundation, Goodis Fund, Sandy Rollman Ovarian Cancer Foundation, Dubrow Fund, Bucks County Board of Associates, and the Mainline Board of Associates.
The paper, “Functional Proteomics Interrogation of the Kinome Identifies MRCKA as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma,” was published in Science Signaling.