The role of polo‐like kinase 3 in the response of BRAF‐mutant cells to targeted anticancer therapies
Open accessAbstract
The activation of oncogenic mitogen‐activated protein kinase cascade via mutations in BRAF is often observed in human melanomas. Targeted inhibitors of BRAF (BRAFi), alone or as a part of a combination therapy, offer a significant benefit to such patients. Unfortunately, some cases are initially nonresponsive to these drugs, while others become refractory in the course of treatment, underscoring the need to understand and mitigate the underlying resistance mechanisms. We report that interference with polo‐like kinase 3 (PLK3) reduces the tolerance of BRAF‐mutant melanoma cells to BRAFi, while increased PLK3 expression has the opposite effect. Accordingly, PLK3 expression correlates with tolerance to BRAFi in a panel of BRAF‐mutant cell lines and is elevated in a subset of recurring BRAFi‐resistant melanomas. In PLK3‐expressing cells, R406, a kinase inhibitor whose targets include PLK3, recapitulates the sensitizing effects of genetic PLK3 inhibitors. The findings support a role for PLK3 as a predictor of BRAFi efficacy and suggest suppression of PLK3 as a way to improve the efficacy of targeted therapy.
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PLK3 confers resistance to the MAPK pathway inhibitor in melanoma.
“PLK3, another member of the PLK1 family, was reported to confer resistance to the MAPK pathway inhibitor in melanoma [44].”
From Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer (2022) · cites this paper as [44]
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- Authors
- Babagana, M., Kichina, J. V., Slabodkin, H., Johnson, S., Maslov, A., Brown, L., Attwood, K., Nikiforov, M. A., & Kandel, E. S.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- Atrium Health Wake Forest Baptist (US)
- Corresponding author
- Kandel, Eugene S.
- Venue
- Molecular Carcinogenesis
- Publisher
- Wiley
- Published
- 2019-09-30
- Volume
- 59
- Issue
- 1
- Pages
- 5-14
- ISSN
- 0899-1987 (ISSN-L)
- 1098-2744
- PMC
- PMC6908756
- OpenAlex
- W2977329298
- Cited by
- 12
- References
- 55
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 1 · 2021: 2 · 2020: 3
- FWCI
- 0.41
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Carcinogenesis (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Roswell Park Alliance Foundation, Roswell Park Cancer Institute
- National Cancer Institute (CA016056, CA137708, CA205178)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- PLK3, BRAF mutation, melanoma, BRAF inhibitors, drug resistance, R406, MAPK signaling, targeted therapy, predictive biomarkers
- MeSH terms
- Vemurafenib, Polo-like Kinases, Animals, Antineoplastic Agents, Humans, Melanoma, Mutation, Gene Expression Regulation, Neoplastic, Mice, SCID, Protein Serine-Threonine Kinases, Tumor Suppressor Proteins, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Molecular Targeted Therapy
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