Pharmacological inhibition of LKB1-NUAK1 signaling in a spheroid model of ovarian cancer metastasis

Sarah McArthur, The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, 790 Commissioners Road East, Room A4 836, London, ON N6A 4L6, Canada; Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 3K7, Canada
Ahmed Abdelhameed, Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Suite 510, Toronto, Ontario M5G 0A3, Canada
Babu Joseph, Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Suite 510, Toronto, Ontario M5G 0A3, Canada.
Methvin Isaac, Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Suite 510, Toronto, Ontario M5G 0A3, Canada
Radek Laufer, Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Suite 510, Toronto, Ontario M5G 0A3, Canada
David E. Uehling, Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Suite 510, Toronto, Ontario M5G 0A3, Canada
Trevor G. Shepherd, The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, 790 Commissioners Road East, Room A4 836, London, ON N6A 4L6, Canada; Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 3K7, Canada; Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 3K7, Canada; Department of Obstetrics and Gynecology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 3K7, Canada.

Author ORCID Identifier

0009000982252

Location

Caesars Windsor Convention Centre, Room: AUGUSTUS III

Event Website

https://wesparkconference.com/

Start Date

22-3-2025 8:00 AM

End Date

22-3-2025 5:30 PM

Description

Epithelial ovarian cancer (EOC) is a lethal gynecologic cancer, usually only diagnosed after widespread metastasis. EOC metastasis is unique, spreading through multicellular aggregates or spheroids. Previously, we demonstrated Liver kinase B1 (LKB1)-NUAK1 signalling promotes spheroid integrity, reattachment, and fibronectin production, in response to bioenergetic stress. Using genetics-based CRISPR deletion cell lines, we have solid evidence that LKB1-NUAK1 signalling plays crucial roles in EOC metastasis, therefore providing new therapeutic targets. The compound ON123300 is an established inhibitor for NUAK1, however, there are no known small molecule inhibitors of LKB1. Working with the OICR, we identified ASC-069 and Dinaciclib as lead compounds, which have been modified to improve LKB1 specificity. This research aims to compare the pharmacologic inhibition of LKB1 and NUAK1 focusing on metastatic properties of EOC spheroids. From our previous studies, and its position upstream in the pathway, we hypothesize LKB1 inhibition will have a greater impact on blocking metastatic properties of EOC spheroids as compared with NUAK1 blockade. Spheroid reattachment assays and Transwell migration/invasion assays will be performed to evaluate LKB1 and NUAK1 inhibition on metastatic properties of spheroids in culture. Early results indicate that spheroid viability and dispersion following reattachment are more potently reduced by LKB1 inhibitors compared to ON123300. We will verify on-target LKB1-NUAK1 inhibitory activity in spheroids; we have preliminary data that fibronectin expression is potently reduced following ON123300 treatment of spheroids. We are the first to develop potential small molecule inhibitors against LKB1 which will be important tools for the field as potential anti-cancer therapeutics.

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Mar 22nd, 8:00 AM Mar 22nd, 5:30 PM

Pharmacological inhibition of LKB1-NUAK1 signaling in a spheroid model of ovarian cancer metastasis

Caesars Windsor Convention Centre, Room: AUGUSTUS III

Epithelial ovarian cancer (EOC) is a lethal gynecologic cancer, usually only diagnosed after widespread metastasis. EOC metastasis is unique, spreading through multicellular aggregates or spheroids. Previously, we demonstrated Liver kinase B1 (LKB1)-NUAK1 signalling promotes spheroid integrity, reattachment, and fibronectin production, in response to bioenergetic stress. Using genetics-based CRISPR deletion cell lines, we have solid evidence that LKB1-NUAK1 signalling plays crucial roles in EOC metastasis, therefore providing new therapeutic targets. The compound ON123300 is an established inhibitor for NUAK1, however, there are no known small molecule inhibitors of LKB1. Working with the OICR, we identified ASC-069 and Dinaciclib as lead compounds, which have been modified to improve LKB1 specificity. This research aims to compare the pharmacologic inhibition of LKB1 and NUAK1 focusing on metastatic properties of EOC spheroids. From our previous studies, and its position upstream in the pathway, we hypothesize LKB1 inhibition will have a greater impact on blocking metastatic properties of EOC spheroids as compared with NUAK1 blockade. Spheroid reattachment assays and Transwell migration/invasion assays will be performed to evaluate LKB1 and NUAK1 inhibition on metastatic properties of spheroids in culture. Early results indicate that spheroid viability and dispersion following reattachment are more potently reduced by LKB1 inhibitors compared to ON123300. We will verify on-target LKB1-NUAK1 inhibitory activity in spheroids; we have preliminary data that fibronectin expression is potently reduced following ON123300 treatment of spheroids. We are the first to develop potential small molecule inhibitors against LKB1 which will be important tools for the field as potential anti-cancer therapeutics.

https://scholar.uwindsor.ca/we-spark-conference/2025/postersessions/131