A RAS-FAM83A Regulatory Loop as a Novel Therapeutic Target for Pancreatic Cancer

描述（由申请人提供）：胰腺癌没有明确的症状，也没有早期检测方法可以筛查这种致命疾病的存在。此外，一旦确定胰腺癌，有限的治疗选择和对化疗的不敏感导致5年生存率约为5%。显然，迫切需要新的治疗方案来延长胰腺癌患者的生命。绝大多数胰腺癌都有KRAS原癌基因的突变，虽然直接抑制突变KRAS的想法一度很有希望，但迄今为止，许多用于阻止突变KRAS活性的抑制剂几乎没有成功。我们在此描述了一种名为FAM83A的新型癌基因，它是ras效应信号（包括MAPK和PI3K/AKT）的关键激活因子。重要的是，与正常胰腺相比，突变RAS表达上调了FAM83A在胰腺癌组织中的表达。在携带KRAS突变体的癌细胞中发现一种能够调控MAPK和PI3K/AKT通路的新癌基因，可能为新的靶向治疗提供一个非凡的机会。重要的是，我们的初步数据表明，消融肿瘤来源细胞（包括胰腺癌）中的FAM83A表达可抑制细胞生长和致瘤性，并抑制MAPK和PI3K/AKT信号传导。目前提出的假设是，ras介导的FAM83A上调和FAM83A介导的MAPK和PI3K/AKT激活形成了一个正反馈回路。为了确定FAM83A在KRAS介导的胰腺细胞转化中的作用，并研究KRAS/FAM83A轴是否将作为胰腺癌的治疗靶点，研究人员制定了以下具体目标。在AIM 1中，我们将定义胰腺癌细胞中FAM83A抑制导致的生物学后果和kras介导的信号变化。利用含有突变体KRAS和升高的FAM83A的胰腺癌细胞，研究FAM83A抑制后突变体KRAS效应激活的生物学后果和变化。在AIM 2中，我们提议确定在胰管上皮细胞（PDEC）转化过程中由FAM83A异常表达激活的ras效应信号。我们拟开展的研究将明确PDEC转化过程中由KRAS介导的FAM83A上调所形成的正反馈回路的重要性，以及突变体KRAS和下游RAS效应物诱导FAM83A转录的机制。了解突变体KRAS、FAM83A、MAPK和PI3K/AKT之间的相互联系将为胰腺癌的发生和发展提供新的见解。此外，本研究发现的新的KRAS/FAM83A反馈回路可能为表达ras的突变胰腺癌细胞提供独特的治疗脆弱性。

DESCRIPTION (provided by applicant): Pancreatic cancer has no clear symptoms and there are no early detection methods available to screen for the presence of this deadly disease. Moreover, once pancreatic cancer is identified, limited treatment options and an insensitivity to chemotherapy result in a 5 year survival rate of ~5%. Clearly, new treatment options are urgently needed to extend the lives of pancreatic cancer patients. The vast majority of pancreatic cancers have mutations in the KRAS proto-oncogene, and while the idea of directly inhibiting mutant KRAS once held promise, to date, the many inhibitors developed to prevent mutant KRAS activity have had little success. We describe here, a novel oncogene named FAM83A that is a key activator of RAS-effector signaling (including MAPK and PI3K/AKT). Importantly, FAM83A is up-regulated by mutant RAS expression and is significantly elevated in pancreatic cancer tissue relative to normal pancreas. The identification of a novel oncogene capable of regulating the MAPK and PI3K/AKT pathways in cancer cells harboring mutant KRAS may provide an extraordinary opportunity for new, targeted therapies. Importantly, our preliminary data demonstrates that ablation of FAM83A expression in tumor-derived cells, including pancreatic cancer, inhibits cell growth and tumorigenicity and suppresses MAPK and PI3K/AKT signaling. The hypothesis of the current proposal is that a positive feedback loop is created by the RAS-mediated up-regulation of FAM83A and the FAM83A-mediated activation of MAPK and PI3K/AKT. To define the role of FAM83A in KRAS-mediated pancreatic cell transformation and examine whether the KRAS/FAM83A axis will serve as a therapeutic target in pancreatic cancer, the following specific aims have been developed. In AIM 1 we will define the biological consequence and KRAS-mediated signaling changes that result from FAM83A suppression in pancreatic cancer cells. Using pancreatic cancer cells harboring mutant KRAS and elevated FAM83A, the biological consequence and changes in mutant KRAS-effector activation will be examined following FAM83A suppression. In AIM 2 we propose to determine the RAS-effector signaling activated by aberrant FAM83A expression during pancreas duct epithelial cell (PDEC) transformation. Our proposed studies will define the importance of the positive feedback loop created by the KRAS-mediated up-regulation of FAM83A during PDEC transformation and the mechanism of FAM83A transcriptional induction by mutant KRAS and downstream RAS effectors. Understanding the interconnections between mutant KRAS, FAM83A, MAPK and PI3K/AKT will provide new insight into pancreatic cancer development and progression. Moreover, the novel KRAS/FAM83A feedback loop uncovered by this study may provide a unique therapeutic vulnerability for mutant RAS-expressing pancreatic cancer cells.