Checkpoint kinase 1 inhibitor + low-dose hydroxyurea efficiently kills BRAF inhibitor- and immune checkpoint inhibitor-resistant melanomas
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Ngo, Hung Long
Proctor, Martina
Rizos, Helen
Dolcetti, Riccardo
Cruz, Jazmina Gonzalez
Wells, James W
Gabrielli, Brian
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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.
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Pigment Cell & Melanoma Research
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© 2023 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Biochemistry and cell biology
Genetics
Oncology and carcinogenesis
CHK1 inhibitor
immune response
replication stress
treatment resistance
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Zeng, Z; Ngo, HL; Proctor, M; Rizos, H; Dolcetti, R; Cruz, JG; Wells, JW; Gabrielli, B, Checkpoint kinase 1 inhibitor + low-dose hydroxyurea efficiently kills BRAF inhibitor- and immune checkpoint inhibitor-resistant melanomas, Pigment Cell & Melanoma Research, 2023