Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jan;37(1):45-50.
doi: 10.1111/pcmr.13120. Epub 2023 Aug 23.

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

Zhen Zeng  1 , Hung Long Ngo  1 , Martina Proctor  1 , Helen Rizos  2 , Riccardo Dolcetti  3 , Jazmina Gonzalez Cruz  4 , James W Wells  4 , Brian Gabrielli  1
Affiliations

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

Zhen Zeng et al. Pigment Cell Melanoma Res. 2024 Jan.

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.

Keywords: CHK1 inhibitor; immune response; replication stress; treatment resistance.

PubMed Disclaimer

References

REFERENCES

    1. Christofyllakis, K., Pföhler, C., Bewarder, M., Müller, C. S. L., Thurner, L., Rixecker, T., Vogt, T., Stilgenbauer, S., Yordanova, K., & Kaddu-Mulindwa, D. (2021). Adjuvant therapy of high-risk (Stages IIC-IV) malignant melanoma in the post interferon-alpha era: A systematic review and meta-analysis. Frontiers in Oncology, 10, 637161.
    1. Czarnecka, A. M., Bartnik, E., Fiedorowicz, M., & Rutkowski, P. (2020). Targeted therapy in melanoma and mechanisms of resistance. International Journal of Molecular Sciences, 21(13), 4576. https://doi.org/10.3390/ijms21134576
    1. Johnson, D. B., Menzies, A. M., Zimmer, L., Eroglu, Z., Ye, F., Zhao, S., Rizos, H., Sucker, A., Scolyer, R. A., Gutzmer, R., Gogas, H., Kefford, R. F., Thompson, J. F., Becker, J. C., Berking, C., Egberts, F., Loquai, C., Goldinger, S. M., Pupo, G. M., … Schadendorf, D. (2015). Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. European Journal of Cancer, 51(18), 2792-2799. https://doi.org/10.1016/j.ejca.2015.08.022
    1. Kim, K. B., Kefford, R., Pavlick, A. C., Infante, J. R., Ribas, A., Sosman, J. A., Fecher, L. A., Millward, M., McArthur, G. A., Hwu, P., Gonzalez, R., Ott, P. A., Long, G. V., Gardner, O. S., Ouellet, D., Xu, Y., DeMarini, D. J., Le, N. T., Patel, K., & Lewis, K. D. (2013). Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. Journal of Clinical Oncology, 31(4), 482-489. https://doi.org/10.1200/jco.2012.43.5966
    1. Lee, J. H., Shklovskaya, E., Lim, S. Y., Carlino, M. S., Menzies, A. M., Stewart, A., Pedersen, B., Irvine, M., Alavi, S., Yang, J. Y. H., Strbenac, D., Saw, R. P. M., Thompson, J. F., Wilmott, J. S., Scolyer, R. A., Long, G. V., Kefford, R. F., & Rizos, H. (2020). Transcriptional downregulation of MHC class I and melanoma de-differentiation in resistance to PD-1 inhibition. Nature Communications, 11(1), 1897. https://doi.org/10.1038/s41467-020-15726-7

Publication types

MeSH terms