Abstract
In ovarian cancer, compacted cell aggregates known as spheroids detach from the primary tumor and enable metastasis within the peritoneum. Targeting this ovarian metastatic cascade motivates a delineation of the morphogenetic pathways governing spheroid shedding and invasion. Here we analyze the role of one of three related Myotonic Dystrophy Kinase-Related CDC42-Binding Kinases (MRCKγ) in ovarian cancer metastasis, and test its potential as a therapeutic target. MRCKs are downstream effectors of Cdc42 and Rac1 GTPases and through activation of myosin-II could produce the mechanical force required during cell invasion. MRCKγ is amplified or mutant in 12.5% of 1680 serous ovarian cancer patient samples in TCGA. Analyses of ovarian cancer SKOV3ip cells with 4-fold overexpression of GFP-Rac1 and increased GTPase activation showed a 1.5-fold increase in MRCKγ protein and a concomitant increase in the phosphorylation of myosin required for contractile force generation. A similar increase in myosin phosphorylation was observed in two OVCAR8 cell lines with overexpression of GFP-Rac1 and GFP-Cdc42, respectively. Analyses of the effects MRCKγ knockdown on ovarian spheroid formation and in mesothelial clearance are in progress. To evaluate the therapeutic potential of MRCK/Cdc42BPs we are also testing their pharmacological inhibition with BDP9066 and SD208 during spheroid formation and mesothelial clearance. Our findings are supported by a recent report showing that inhibition of the related MRCKα kinase blocks ovarian cancer cell spheroid formation in vitro. By the end of these studies we will have a better understanding of the role of MRCK/Cdc42BPs in ovarian cancer metastatic pathway, and a potential therapeutic target for ovarian cancer treatment.
Citation Format: Leslie Toledo-Jacobo. Regulatory role of MRCK gamma in ovarian cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2297.
