Defining BRCA replication dysfunction in therapy response

这项资助的目标是利用对肿瘤脆弱性的新理解， 遗传性乳腺癌基因我们已经发现，缺乏BRCA途径基因的细胞， 对DNA复制扰动（应激）作出反应，因此复制没有受到适当的限制， ssDNA区域（缺口）形成。我们发现，当缺口存在时，BRCA癌细胞对治疗敏感， 并且当间隙被避免时，出现电阻。我们的发现是，差距对于治疗反应至关重要， 当前框架的范式转变，提出持续的DNA断裂和分叉退化是 因为敏感。因此，我们建议采用最先进的实验来绘制分子决定簇 这种BRCA通路分叉抑制功能的一部分此外，将确定差距，使机械，是至关重要的 治疗反应和对治疗抵抗至关重要的差距回避机制。最后，我们将重新- 检查先前归因于恢复的DNA修复和叉保护的治疗抗性模型， 确定间隙抑制是否是基本的阻力机制。总体而言，这些建议 研究将确定癌细胞如何屈服于并最终获得对化疗的抵抗力， 对预测耐药性的生物标志物和预防耐药性的药物有价值的见解。

The goal of this grant is to harness a new understanding of vulnerabilities in tumors with mutations in the hereditary breast cancer genes. We have found that cells deficient in the BRCA-pathway genes, fail to properly respond to DNA replication perturbations (stress) and consequently replication is not restrained properly and ssDNA regions (gaps) develop. We find that when gaps are present, BRCA cancer cells are sensitive to therapy and when gaps are avoided, resistance occurs. Our findings that gaps are fundamental to therapy response is a paradigm shift in the current framework that proposes that persistent DNA breaks and fork degradation is the cause of sensitivity. Thus, we propose to employ state-of-the-art experiments to map the molecular determinants of this BRCA pathway fork restraint function. Moreover, will identify the gap making machinery that is critical for therapy response and the gap avoidance machinery that is critical to therapy resistance. Lastly, we will re- examine models of therapy resistance previously attributed to restored DNA repair and fork protection and determine if gap suppression is instead the fundamental resistance mechanism. Collectively, these proposed studies will identify how cancer cells succumb to and eventually gain resistance to chemotherapy and provide valuable insight towards biomarkers predicting resistance and drugs that prevent resistance.