Abstract C189: Defective S phase cell cycle checkpoint: A potential culprit and target in melanoma

Abstract

Abstract The S phase cell cycle checkpoint is critical for maintaining genomic integrity. This checkpoint is triggered in response to DNA damage and replication stresses to control cell cycle progression, halting DNA replication and allowing the time to repair to maintain genomic integrity. If this checkpoint is defective, cells lose their ability to ensure the fidelity of replication and repair any damage, resulting in replicative stress and genomic instability which will subsequently increase the risk of cancer. We have discovered that a large proportion of melanoma cell lines lose the ability to halt replication when challenged with high dose hydroxyurea-induced replicative stress, despite normal cell cycle checkpoint signalling. We found that failure in the crosstalk between ATR-CHK1 checkpoint signalling and the cell cycle mechanism in destabilization of CDC25A. Although CHK1-dependent phosphorylation of CDC25A which triggers its degradation was detected, the S phase checkpoint defective melanoma cell lines fail to destabilize CDC25A, maintaining normal activation of CDK2/Cyclin E. The melanoma cells with this S phase checkpoint defect are also hyper-sensitive to killing by CHK1 inhibitor. We have previously shown that melanoma with high levels of replicative stress are very sensitive to CHK1 inhibitors. I will report our studies investigating whether CHK1 inhibitor sensitivity is a direct outcome of the replicative stress arising from the S phase checkpoint defect, or whether the loss of the ATR-CHK1-CDC25A dependent S phase checkpoint signalling mechanism is directly responsible for the hyper-sensitivity to CHK1 inhibitors. Citation Format: Zay Y. Oo, Sheena Daignault, James Chen, Brian Gabrielli. Defective S phase cell cycle checkpoint: A potential culprit and target in melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C189.