Illuminating the functions and translational potential of CDC42BP/MRCK kinases in ovarian cancer

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PROJECT SUMMARY This proposal will examine the function and targeting potential of three related serine threonine kinases in the context of serous ovarian cancer – a rare disease with need for improved therapies. The selected kinases are significant because they are direct effector proteins and selective mediators of Rac1 and Cdc42 (not Rho A) GTPase signaling pathways with import in ovarian cancer metastasis and poor outcomes, as well as in normal neurodevelopment and inherited disorders. A large fraction of the over 8000 kinases curated by Pharos are involved in human disease, yet are understudied (6850 Tdark or Tbio targets) and have no small molecules meeting the criteria for clinical translation (activity at ≤ 30 nM). Among these kinases, the Cdc42 binding protein A, B and G kinases (MRCK α, β and γ) remain unrealized as targets due to the dearth of knowledge regarding their specific functions in biological processes and disease states. Our team first demonstrated hyperactivity and overexpression of Rac1 and Cdc42 in ovarian cancer patients, and the utility of a repurposed drug dually targeting Rac1 and Cdc42. Because the GTPases serve as a nexus for integrating multiple signaling cascades, we hypothesize that the Cdc42 binding protein kinases mediate the downstream adverse consequences of aberrant Rac1/Cdc42 activity in ovarian cancer. Our goals are to comparatively delineate the functions of Cdc42 binding proteins A, B and G in the ovarian cancer metastatic process (Aim1) and evaluate the therapeutic potential of individual Cdc42 binding protein inhibition, alone and in combination with selective Rac1/Cdc42 inhibition (Aim 2). In keeping with the RFA the planned studies will 1) increase biochemical, cellular, and animal model evidence of disease/physiological relevance for the selected proteins, 2) elucidate the functions of the understudied proteins in models that will inform normal functions and disruptions leading to human disease and 3) provide critical information on the therapeutic potential of Tbio kinase targets. Our selection of Cdc42 binding proteins A, B and G is based on their roles as direct effector proteins for Rac1/Cdc42 signaling, evidence for moderate to high expression in the ovary and frequent detection in ovarian cancer. Furthermore, our findings show that selective targeting of Rac1/Cdc42 provides anti-cancer activities in patient-derived ovarian tumor cells and survival benefit in animal models thereby supporting the potential significance of one or more of the Cdc42 binding proteins in this disease. In sum, it is expected that illumination of Cdc42 binding protein functions will be relevant to dysregulation in ovarian and other cancers as well as to neurodevelopmental and non-cancerous diseases. Delineation of the non-redundant functions of each family member are highly relevant to drug discovery and therapeutic development.