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Out of the dark, a new kinase target in ovarian cancer
Ovarian cancer is frequently fatal; it is difficult to detect and challenging to treat. Uncovering genetic signatures has done little to improve clinical outcomes. Using cell lines and patient tumors, Kurimchak et al. analyzed the functional kinome of high-grade serous ovarian carcinoma (HGSOC) and identified a relatively uncharacterized kinase called MRCKA, among potentially others, as being important for HGSOC cell survival and tumor growth. Decreasing MRCKA abundance or pharmacologically inhibiting its kinase activity killed HGSOC cells but, as with so many growth inhibitors, led to activation of other survival-promoting kinases in remaining cells. Cotargeting one of these (PAK1) or cotreating cells with platinum-based chemotherapy had greater cytotoxicity. The findings identify multiple potential therapeutic strategies to treat HGSOC and prevent drug resistance in patients.
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer with few effective, targeted therapies. HGSOC tumors exhibit genomic instability with frequent alterations in the protein kinome; however, only a small fraction of the kinome has been therapeutically targeted in HGSOC. Using multiplexed inhibitor beads and mass spectrometry, we mapped the kinome landscape of HGSOC tumors from patients and patient-derived xenograft models. The data revealed a prevalent signature consisting of established HGSOC driver kinases, as well as several kinases previously unexplored in HGSOC. Loss-of-function analysis of these kinases in HGSOC cells indicated MRCKA (also known as CDC42BPA) as a putative therapeutic target. Characterization of the effects of MRCKA knockdown in established HGSOC cell lines demonstrated that MRCKA was integral to signaling that regulated the cell cycle checkpoint, focal adhesion, and actin remodeling, as well as cell migration, proliferation, and survival. Moreover, inhibition of MRCKA using the small-molecule BDP9066 decreased cell proliferation and spheroid formation and induced apoptosis in HGSOC cells, suggesting that MRCKA may be a promising therapeutic target for the treatment of HGSOC.
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