Abstract C59: Role of MTH1 (NUTD1) in cancer cell survival

Human mutT homolog MTH1 (also known as NUDT1) is a purine nucleoside triphosphatase which hydrolyses oxidised nucleotides (8-oxo-dGTP and 2-OH-dATP) into mono-phosphate forms to prevent these damaged bases from being incorporated into DNA. Recent studies have suggested a key role of MTH1 in the survival of cancer cells. It was hypothesized that in cancer cells with high levels of reactive oxygen species (ROS), small molecule inhibition or loss of MTH1 would lead to accumulation of oxidised nucleotides in DNA, increased genome instability and loss of cell viability. In order to validate MTH1 as a potential cancer therapeutic target we have developed additional potent small molecule inhibitors of MTH1 and generated siRNA knock-down and CRISPR-mediated knock-out cell lines. Using these tools we evaluated the impact of either MTH1 inhibition or loss of expression on cell viability, proliferation, induction of DNA damage and cell cycle arrest across multiple cell lines in vitro. While we have confirmed that the previous study compounds (TH588, TH287, (S)-crizotinib) are potent inhibitors of MTH1 and have broad cancer cell line growth inhibition activity, we were unable to demonstrate a corresponding induction of H2AX, 53BP1 or phospho-ATM DNA damage response (DDR). In addition none of our MTH1 inhibitors were able to show significant growth inhibitory activity across cell lines panels or induce a DDR despite being able to potently engage MTH1 in cells as evidenced by cell thermal ...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: DNA Repair and Modulation: Poster Presentations - Proffered Abstracts Source Type: research