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Molecular Cancer Therapeutics
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Cancer Biology and Translational Studies

PLK1 and NOTCH Positively Correlate in Melanoma and Their Combined Inhibition Results in Synergistic Modulations of Key Melanoma Pathways

Shengqin Su, Gagan Chhabra, Mary A. Ndiaye, Chandra K. Singh, Ting Ye, Wei Huang, Colin N. Dewey, Vijayasaradhi Setaluri and Nihal Ahmad
Shengqin Su
1Department of Dermatology, University of Wisconsin, Madison, Wisconsin.
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Gagan Chhabra
1Department of Dermatology, University of Wisconsin, Madison, Wisconsin.
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Mary A. Ndiaye
1Department of Dermatology, University of Wisconsin, Madison, Wisconsin.
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Chandra K. Singh
1Department of Dermatology, University of Wisconsin, Madison, Wisconsin.
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Ting Ye
2Department of Statistics, University of Wisconsin, Madison, Wisconsin.
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Wei Huang
3Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin.
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Colin N. Dewey
4Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin.
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Vijayasaradhi Setaluri
1Department of Dermatology, University of Wisconsin, Madison, Wisconsin.
5William S. Middleton VA Medical Center, Madison, Wisconsin.
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Nihal Ahmad
1Department of Dermatology, University of Wisconsin, Madison, Wisconsin.
5William S. Middleton VA Medical Center, Madison, Wisconsin.
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  • For correspondence: nahmad@wisc.edu
DOI: 10.1158/1535-7163.MCT-20-0654 Published January 2021
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Abstract

Melanoma is one of the most serious forms of skin cancer, and its increasing incidence coupled with nonlasting therapeutic options for metastatic disease highlights the need for additional novel approaches for its management. In this study, we determined the potential interactions between polo-like kinase 1 (PLK1, a serine/threonine kinase involved in mitotic regulation) and NOTCH1 (a type I transmembrane protein deciding cell fate during development) in melanoma. Employing an in-house human melanoma tissue microarray (TMA) containing multiple cases of melanomas and benign nevi, coupled with high-throughput, multispectral quantitative fluorescence imaging analysis, we found a positive correlation between PLK1 and NOTCH1 in melanoma. Furthermore, The Cancer Genome Atlas database analysis of patients with melanoma showed an association of higher mRNA levels of PLK1 and NOTCH1 with poor overall, as well as disease-free, survival. Next, utilizing small-molecule inhibitors of PLK1 and NOTCH (BI 6727 and MK-0752, respectively), we found a synergistic antiproliferative response of combined treatment in multiple human melanoma cells. To determine the molecular targets of the overall and synergistic responses of combined PLK1 and NOTCH inhibition, we conducted RNA-sequencing analysis employing a unique regression model with interaction terms. We identified the modulations of several key genes relevant to melanoma progression/metastasis, including MAPK, PI3K, and RAS, as well as some new genes such as Apobec3G, BTK, and FCER1G, which have not been well studied in melanoma. In conclusion, our study demonstrated a synergistic antiproliferative response of concomitant targeting of PLK1 and NOTCH in melanoma, unraveling a potential novel therapeutic approach for detailed preclinical/clinical evaluation.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:161–72

  • Received August 1, 2020.
  • Revision received September 24, 2020.
  • Accepted October 23, 2020.
  • Published first November 11, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (1)
January 2021
Volume 20, Issue 1
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PLK1 and NOTCH Positively Correlate in Melanoma and Their Combined Inhibition Results in Synergistic Modulations of Key Melanoma Pathways
Shengqin Su, Gagan Chhabra, Mary A. Ndiaye, Chandra K. Singh, Ting Ye, Wei Huang, Colin N. Dewey, Vijayasaradhi Setaluri and Nihal Ahmad
Mol Cancer Ther January 1 2021 (20) (1) 161-172; DOI: 10.1158/1535-7163.MCT-20-0654

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PLK1 and NOTCH Positively Correlate in Melanoma and Their Combined Inhibition Results in Synergistic Modulations of Key Melanoma Pathways
Shengqin Su, Gagan Chhabra, Mary A. Ndiaye, Chandra K. Singh, Ting Ye, Wei Huang, Colin N. Dewey, Vijayasaradhi Setaluri and Nihal Ahmad
Mol Cancer Ther January 1 2021 (20) (1) 161-172; DOI: 10.1158/1535-7163.MCT-20-0654
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Molecular Cancer Therapeutics
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