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

Abstract

AbstractTreatment 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.