Checkpoint kinase 1 inhibitor + low-dose hydroxyurea efficiently kills BRAF inhibitor- and immune checkpoint inhibitor-resistant melanomas

Zhen Zeng; Hung Long Ngo; Martina Proctor; Helen Rizos; Riccardo Dolcetti; Jazmina Gonzalez Cruz; James W. Wells; Brian Gabrielli

doi:10.1111/pcmr.13120

Checkpoint kinase 1 inhibitor + low-dose hydroxyurea efficiently kills BRAF inhibitor- and immune checkpoint inhibitor-resistant melanomas

Zhen Zeng, Hung Long Ngo, Martina Proctor, Helen Rizos, Riccardo Dolcetti, Jazmina Gonzalez Cruz, James W. Wells, Brian Gabrielli^*

^*Corresponding author for this work

Macquarie Medical School

Research output: Contribution to journal › Article › peer-review

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Abstract

Treatment of melanomas with targeted and immunotherapies has proven effective, but resistance to both treatments is a common outcome leaving a high proportion of patients without effective alternative treatment options. Replication stress is a common feature of melanomas, and this is effectively targeted using a combination of checkpoint kinase 1 (CHK1) inhibitor and low-dose hydroxyurea (LDHU). This combination also promotes inflammatory and anti-tumour immune responses in vivo. Melanoma cell lines resistant to BRAF inhibitor (BRAFi) or immune checkpoint inhibitors (ICI) retain their sensitivity to CHK1i + LDHU, with sensitivity similar to that of parental tumours. In vivo, BRAFi-resistant and BRAFi-sensitive parental tumours produce an identical immune response with treatment.

Original language	English
Pages (from-to)	45-50
Number of pages	6
Journal	Pigment Cell and Melanoma Research
Volume	37
Issue number	1
Early online date	23 Aug 2023
DOIs	https://doi.org/10.1111/pcmr.13120
Publication status	Published - Jan 2024

Bibliographical note

Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

CHK1 inhibitor
immune response
replication stress
treatment resistance

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10.1111/pcmr.13120Licence: CC BY

Publisher version (open access)Final published version, 2.03 MBLicence: CC BY

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title = "Checkpoint kinase 1 inhibitor + low-dose hydroxyurea efficiently kills BRAF inhibitor- and immune checkpoint inhibitor-resistant melanomas",

abstract = "Treatment of melanomas with targeted and immunotherapies has proven effective, but resistance to both treatments is a common outcome leaving a high proportion of patients without effective alternative treatment options. Replication stress is a common feature of melanomas, and this is effectively targeted using a combination of checkpoint kinase 1 (CHK1) inhibitor and low-dose hydroxyurea (LDHU). This combination also promotes inflammatory and anti-tumour immune responses in vivo. Melanoma cell lines resistant to BRAF inhibitor (BRAFi) or immune checkpoint inhibitors (ICI) retain their sensitivity to CHK1i + LDHU, with sensitivity similar to that of parental tumours. In vivo, BRAFi-resistant and BRAFi-sensitive parental tumours produce an identical immune response with treatment.",

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AU - Zeng, Zhen

AU - Ngo, Hung Long

AU - Proctor, Martina

AU - Rizos, Helen

AU - Dolcetti, Riccardo

AU - Cruz, Jazmina Gonzalez

AU - Wells, James W.

AU - Gabrielli, Brian

N1 - Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2024/1

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N2 - Treatment of melanomas with targeted and immunotherapies has proven effective, but resistance to both treatments is a common outcome leaving a high proportion of patients without effective alternative treatment options. Replication stress is a common feature of melanomas, and this is effectively targeted using a combination of checkpoint kinase 1 (CHK1) inhibitor and low-dose hydroxyurea (LDHU). This combination also promotes inflammatory and anti-tumour immune responses in vivo. Melanoma cell lines resistant to BRAF inhibitor (BRAFi) or immune checkpoint inhibitors (ICI) retain their sensitivity to CHK1i + LDHU, with sensitivity similar to that of parental tumours. In vivo, BRAFi-resistant and BRAFi-sensitive parental tumours produce an identical immune response with treatment.

AB - Treatment of melanomas with targeted and immunotherapies has proven effective, but resistance to both treatments is a common outcome leaving a high proportion of patients without effective alternative treatment options. Replication stress is a common feature of melanomas, and this is effectively targeted using a combination of checkpoint kinase 1 (CHK1) inhibitor and low-dose hydroxyurea (LDHU). This combination also promotes inflammatory and anti-tumour immune responses in vivo. Melanoma cell lines resistant to BRAF inhibitor (BRAFi) or immune checkpoint inhibitors (ICI) retain their sensitivity to CHK1i + LDHU, with sensitivity similar to that of parental tumours. In vivo, BRAFi-resistant and BRAFi-sensitive parental tumours produce an identical immune response with treatment.

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KW - immune response

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ER -

Checkpoint kinase 1 inhibitor + low-dose hydroxyurea efficiently kills BRAF inhibitor- and immune checkpoint inhibitor-resistant melanomas

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