Targeting replication stress avoidance in cancer

摘要 这项提案的总体目标是了解和靶向癌细胞对压力耐受性的依赖 途径。我们发现癌细胞通过参与一种称为 经损伤合成（TLS）。通过使用TLS，癌细胞能够以连续的方式复制 并破坏复制应激反应。在这里，我们建议实施最先进的测定， 分析癌细胞如何改变DNA复制叉动力学和复制体组分以促进TLS。 通过定义核心TLS机制，我们将寻求识别TLS的生物标志物和新靶点。 重要的是，我们已经开发了一种TLS的小分子抑制剂，可以选择性地阻止DNA复制。 几种依赖TLS的癌细胞系。此外，我们发现，殖民地形成潜力 TLS依赖性癌细胞在抑制TLS后显著减少。因此，我们建议确定 使用细胞筛选和数据库分析的TLS依赖性癌症的范围。此外，为了进一步充分 为了开发TLS抑制的治疗潜力，我们建议测量和改善TLS抑制的抗癌效果， 我们的铅小分子的潜力。总的来说，这些拟议中的研究将确定癌细胞是如何 参与TLS以及如何最好地阻止TLS以选择性地靶向癌症。

Abstract The overall goal of this proposal is to understand and target cancer cell addictions to stress- tolerance pathways. We have discovered that cancer cells maintain proliferation by engaging in a pathway known as translesion synthesis (TLS). By employing TLS, cancer cells are able to replicate in a continuous manner and subvert the replication stress response. Here, we propose to implement state-of-the-art assays to analyze how cancer cells alter DNA replication fork dynamics and replisome components to promote TLS. By defining the core TLS machinery, we will seek to identify biomarkers and novel targets of TLS. Importantly, we have developed a small molecule inhibitor of TLS that selectively halts DNA replication in several cancer cell lines that are dependent on TLS. Moreover, we found that the colony forming potential of TLS-dependent cancer cells is dramatically reduced upon inhibition of TLS. Thus, we propose to identify the scope of TLS dependent cancers using cell screening and data base analysis. In addition, to fully further develop the therapeutic potential of TLS inhibition, we propose to measure and improve the anti- cancer potential of our lead small molecules. Collectively, these proposed studies will identify how cancer cells engage TLS and how best to block TLS to selectively target cancer.