Checkpoint Kinase 1 Inhibitor Combined with Low Dose Hydroxyurea Promotes ATM-Activated NF-κB-Dependent Pro-Inflammatory Chemokine Expression in Melanomas

TL;DR

A new treatment for melanoma kills cancer cells and boosts immune response by increasing pro-inflammatory chemokines.

Contribution

The study identifies the ATM-NF-κB pathway as the mechanism for chemokine upregulation by CHK1i and hydroxyurea.

Findings

SRA737 + LDHU increases pro-inflammatory chemokine expression in melanoma cells.

The ATM-NF-κB pathway is responsible for the upregulation of chemokines by the treatment.

NF-κB and ATM inhibition does not affect the treatment's ability to kill melanoma cells.

Abstract

Tumours avoid detection by the body’s immune system through a range of mechanisms. An anti-cancer treatment that can alter this tumour-induced immune avoidance could enhance the ability of the patient’s own immune system to detect and respond appropriately to the tumour. Here, we show that a novel treatment that directly kills melanoma also upregulates chemokines, agents that can attract immune cells into the tumour to enhance an anti-tumour immune response. The mechanism by which this treatment increases these chemokines is also determined and involves a response to damage caused by the treatment that is also responsible for the tumour cell killing by this treatment. This study demonstrates that the new treatment can not only directly and effectively kill melanoma cells but also promote signals that will encourage immune cells to recognise the tumour.

Background/Objectives: Melanoma has a rising incidence worldwide. Current treatments are effective, although the development of resistance is common. A novel anti-cancer treatment using checkpoint kinase 1 inhibitor (CHK1i), SRA737, in combination with low-dose hydroxyurea (LDHU), has been demonstrated to effectively kill tumour cells and promote an anti-tumour immune response through the treatment-induced release of pro-inflammatory chemokines and cytokines. These chemokines/cytokines modify the tumour microenvironment from an immunosuppressive to an inflamed state to recruit anti-tumour immune cells. Methods: A panel of human melanoma cell lines was assessed using a panel of chemokines and cytokine expression, and the mechanism of their regulation was investigated. Results: We demonstrate that SRA737 + LDHU upregulates pro-inflammatory chemokines in human melanoma cells in response to SRA737 + LDHU through the ATM-NF-κB signalling pathway. The increased chemokine expression corresponded to the increase in secretion of pro-inflammatory chemokines from tumour cells following SRA737 + LDHU treatment. However, inhibiting NF-κB and ATM did not affect SRA737 + LDHU-induced cell killing. Increased expression of non-NF-κB target genes with SRA737 + LDHU suggests that other transcriptional pathways are also activated and may contribute to the increasing cytokine/chemokine gene expression in response to treatment. Conclusions: SRA737 + LDHU upregulates pro-inflammatory chemokine expression through an ATM-NF-κB-dependent mechanism.

Figures