Abstract A069: Increasing replication stress by reducing nucleoside levels sensitizes melanomas and non-small cell lung cancers to CHK1 inhibitor in vitro and in vivo

Abstract

Abstract CHK1 inhibitors are being investigated as chemosensitizing agents with agents that increase replication stress. Here we have investigated the molecular basis of sensitivity to CHK1 inhibitors as single agents in melanoma and as combinations with subclinical doses of hydroxyurea in melanoma and non-small cell lung cancer (NSCLC). We have found that sensitivity in vitro and in vivo to single agent CHK1 inhibitor is associated with defective S phase cell cycle checkpoint response to low dNTP levels. Loss of checkpoint response by overexpressing components of the checkpoint or inhibition of Wee1, convert CHK1 inhibitor insensitive cells to sensitive, and similarly depletion of CDC25A reduces CHK1 inhibitor sensitivity in sensitive lines. The increased DNA damage found with CHK1 inhibitor treatment is not sufficient to induce cell death, and cell death was triggered without entry into mitosis. We have found that about 20% of melanomas are sensitive to CHK1 inhibitor as a single agent, but we show that >70% of melanomas and NSCLCs are sensitive to combination with subclinical doses of hydroxyurea. The mechanism of cell death in the combination appears identical to CHK1 inhibitor alone in inhibitor-sensitive melanomas, with cells dying without entering mitosis. In half the cell melanomas tested, the combination produced a complete loss of viability; in the other half, the viable population after treatment was incapable of further proliferation in the absence in drug. The sensitivity to the combination is independent of other known risk factors, suggesting a significant proportion of melanoma and lung cancer patients could benefit from treatment with this drug combination. Citation Format: Zay Yar Oo, Martina Proctor, Alexander Stevenson, Jill Larsen, Brian G. Gabrielli. Increasing replication stress by reducing nucleoside levels sensitizes melanomas and non-small cell lung cancers to CHK1 inhibitor in vitro and in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A069.