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

> **NIH NIH R03** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2021 · $151,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10216717
- **Project number:** 1R03TR003324-01A1
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** LAURIE G HUDSON
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $151,500
- **Award type:** 1
- **Project period:** 2021-04-15 → 2022-10-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216717

## Citation

> US National Institutes of Health, RePORTER application 10216717, Illuminating the functions and translational potential of CDC42BP/MRCK kinases in ovarian cancer (1R03TR003324-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216717. Licensed CC0.

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