Targeting replication stress avoidance in cancer

摘要 这项提案的总体目标是了解和瞄准癌细胞对压力耐受性的上瘾。 小路。我们已经发现，癌细胞通过参与一条称为 跨损伤合成(TLS)。通过使用TLS，癌细胞能够以连续的方式复制 并颠覆复制应激反应。在这里，我们建议实施最先进的分析来 分析癌细胞如何改变DNA复制分叉动力学和复制体组分以促进TLS。 通过定义TLS的核心机制，我们将寻求识别TLS的生物标记物和新靶点。 重要的是，我们已经开发出一种TLS的小分子抑制剂，它可以选择性地阻止DNA在 几种依赖TLS的癌细胞株。此外，我们还发现，菌落形成潜力 抑制TLS后，依赖TLS的癌细胞显著减少。因此，我们建议确定 应用细胞筛选和数据库分析确定TLS依赖型癌症的范围。此外，要充分进一步 开发TLS抑制的治疗潜力，我们建议测量和提高抗癌 我们的铅小分子的潜力。总的来说，这些拟议的研究将确定癌细胞如何 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.