WEE1 kinase inhibitor MK-1775 sensitizes oral tongue squamous cell carcinoma cells to radiation irrespective of TP53 status

Aisha Hussein Al-Jamaei; Jan G.A.M. de Visscher; V. Ramadugula Subramanyam; Tymour Forouzanfar; Peter Sminia; Behrouz Zandieh Doulabi; Marco N. Helder

doi:10.1111/odi.14269

WEE1 kinase inhibitor MK-1775 sensitizes oral tongue squamous cell carcinoma cells to radiation irrespective of TP53 status

Aisha Hussein Al-Jamaei, Jan G.A.M. de Visscher, V. Ramadugula Subramanyam, Tymour Forouzanfar, Peter Sminia, Behrouz Zandieh Doulabi, Marco N. Helder^*

^*Corresponding author for this work

Maxillofacial Surgery

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

OBJECTIVE: Oral tongue squamous cell carcinoma (OTSCC) frequently harbors non-functional p53 and depends on G2/M checkpoint mediated by WEE1. WEE1 suppression has been identified as a promising anti-tumor strategy. This study investigated the capacity of WEE1 kinase inhibitor (MK-1775) and its underlying mechanisms in enhancing radiation responses of OTSCC cells in vitro.

MATERIALS AND METHODS: WEE1 kinase expression and its downstream target (CDK1) were investigated in OTSCC versus normal oral tissue. A synergistic combination of MK-1775 with radiation on OTSCC cell lines with different p53 statuses was assessed by viability assay. The radio-sensitizing effects of MK-1775 on apoptosis, cell cycle, DNA damage, and mitotic entry were also determined.

RESULTS: Irradiation enhanced CDK1 expression in all tested cell lines, though the effect was far more pronounced in p53 mutated cell lines. MK-1775 exhibited inhibitory effects against the survival of all cell lines and enhanced their response to the radiation. These effects were strongly elicited by induction of apoptosis and lethal mitosis, but less likely by abrogation of radiation-induced G2 arrest.

CONCLUSION: These results demonstrate the efficacy of MK-1775 in enhancing the radiation effect on OTSCC in vitro associated with a significant apoptotic death rate, identifying WEE1 inhibitor as a potent radiosensitizer in OTSCC irrespective of p53 mutational status.

Original language	English
Pages (from-to)	2640-2649
Number of pages	10
Journal	Oral Diseases
Volume	29
Issue number	7
Early online date	7 Jun 2022
DOIs	https://doi.org/10.1111/odi.14269
Publication status	Published - Oct 2023

Bibliographical note

Publisher Copyright:
© 2022 The Authors. Oral Diseases published by Wiley Periodicals LLC.

Funding

The authors are grateful to Dr.Prasannasrinivas Deshpande of JSS Dental College and Hospital, Mysore, India for his help in editing the manuscript. The authors are grateful to Sander Snel from the hematology department, Cancer Center Amsterdam (CCA) for his help in some experiments.

Keywords

MK-1775
Oral tongue squamous cell carcinoma
p53
radiation
radiosensitization
Wee1 kinase inhibitor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/odi.14269

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title = "WEE1 kinase inhibitor MK-1775 sensitizes oral tongue squamous cell carcinoma cells to radiation irrespective of TP53 status",

abstract = "OBJECTIVE: Oral tongue squamous cell carcinoma (OTSCC) frequently harbors non-functional p53 and depends on G2/M checkpoint mediated by WEE1. WEE1 suppression has been identified as a promising anti-tumor strategy. This study investigated the capacity of WEE1 kinase inhibitor (MK-1775) and its underlying mechanisms in enhancing radiation responses of OTSCC cells in vitro.MATERIALS AND METHODS: WEE1 kinase expression and its downstream target (CDK1) were investigated in OTSCC versus normal oral tissue. A synergistic combination of MK-1775 with radiation on OTSCC cell lines with different p53 statuses was assessed by viability assay. The radio-sensitizing effects of MK-1775 on apoptosis, cell cycle, DNA damage, and mitotic entry were also determined.RESULTS: Irradiation enhanced CDK1 expression in all tested cell lines, though the effect was far more pronounced in p53 mutated cell lines. MK-1775 exhibited inhibitory effects against the survival of all cell lines and enhanced their response to the radiation. These effects were strongly elicited by induction of apoptosis and lethal mitosis, but less likely by abrogation of radiation-induced G2 arrest.CONCLUSION: These results demonstrate the efficacy of MK-1775 in enhancing the radiation effect on OTSCC in vitro associated with a significant apoptotic death rate, identifying WEE1 inhibitor as a potent radiosensitizer in OTSCC irrespective of p53 mutational status.",

keywords = "MK-1775, Oral tongue squamous cell carcinoma, p53, radiation, radiosensitization, Wee1 kinase inhibitor",

author = "Al-Jamaei, {Aisha Hussein} and {de Visscher}, {Jan G.A.M.} and Subramanyam, {V. Ramadugula} and Tymour Forouzanfar and Peter Sminia and Doulabi, {Behrouz Zandieh} and Helder, {Marco N.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Oral Diseases published by Wiley Periodicals LLC.",

year = "2023",

month = oct,

doi = "10.1111/odi.14269",

language = "English",

volume = "29",

pages = "2640--2649",

journal = "Oral Diseases",

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T1 - WEE1 kinase inhibitor MK-1775 sensitizes oral tongue squamous cell carcinoma cells to radiation irrespective of TP53 status

AU - Al-Jamaei, Aisha Hussein

AU - de Visscher, Jan G.A.M.

AU - Subramanyam, V. Ramadugula

AU - Forouzanfar, Tymour

AU - Sminia, Peter

AU - Doulabi, Behrouz Zandieh

AU - Helder, Marco N.

PY - 2023/10

Y1 - 2023/10

N2 - OBJECTIVE: Oral tongue squamous cell carcinoma (OTSCC) frequently harbors non-functional p53 and depends on G2/M checkpoint mediated by WEE1. WEE1 suppression has been identified as a promising anti-tumor strategy. This study investigated the capacity of WEE1 kinase inhibitor (MK-1775) and its underlying mechanisms in enhancing radiation responses of OTSCC cells in vitro.MATERIALS AND METHODS: WEE1 kinase expression and its downstream target (CDK1) were investigated in OTSCC versus normal oral tissue. A synergistic combination of MK-1775 with radiation on OTSCC cell lines with different p53 statuses was assessed by viability assay. The radio-sensitizing effects of MK-1775 on apoptosis, cell cycle, DNA damage, and mitotic entry were also determined.RESULTS: Irradiation enhanced CDK1 expression in all tested cell lines, though the effect was far more pronounced in p53 mutated cell lines. MK-1775 exhibited inhibitory effects against the survival of all cell lines and enhanced their response to the radiation. These effects were strongly elicited by induction of apoptosis and lethal mitosis, but less likely by abrogation of radiation-induced G2 arrest.CONCLUSION: These results demonstrate the efficacy of MK-1775 in enhancing the radiation effect on OTSCC in vitro associated with a significant apoptotic death rate, identifying WEE1 inhibitor as a potent radiosensitizer in OTSCC irrespective of p53 mutational status.

AB - OBJECTIVE: Oral tongue squamous cell carcinoma (OTSCC) frequently harbors non-functional p53 and depends on G2/M checkpoint mediated by WEE1. WEE1 suppression has been identified as a promising anti-tumor strategy. This study investigated the capacity of WEE1 kinase inhibitor (MK-1775) and its underlying mechanisms in enhancing radiation responses of OTSCC cells in vitro.MATERIALS AND METHODS: WEE1 kinase expression and its downstream target (CDK1) were investigated in OTSCC versus normal oral tissue. A synergistic combination of MK-1775 with radiation on OTSCC cell lines with different p53 statuses was assessed by viability assay. The radio-sensitizing effects of MK-1775 on apoptosis, cell cycle, DNA damage, and mitotic entry were also determined.RESULTS: Irradiation enhanced CDK1 expression in all tested cell lines, though the effect was far more pronounced in p53 mutated cell lines. MK-1775 exhibited inhibitory effects against the survival of all cell lines and enhanced their response to the radiation. These effects were strongly elicited by induction of apoptosis and lethal mitosis, but less likely by abrogation of radiation-induced G2 arrest.CONCLUSION: These results demonstrate the efficacy of MK-1775 in enhancing the radiation effect on OTSCC in vitro associated with a significant apoptotic death rate, identifying WEE1 inhibitor as a potent radiosensitizer in OTSCC irrespective of p53 mutational status.

KW - MK-1775

KW - Oral tongue squamous cell carcinoma

KW - p53

KW - radiation

KW - radiosensitization

KW - Wee1 kinase inhibitor

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WEE1 kinase inhibitor MK-1775 sensitizes oral tongue squamous cell carcinoma cells to radiation irrespective of TP53 status

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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