Targeting K-Ras effector signaling for pancreatic cancer treatment

描述(申请人提供)：突变的KRAS可以被认为是治疗胰腺导管腺癌(PDAC)的最重要的治疗靶点。PDAC的唯一定义是KRAS中~100%的致癌突变发生率。虽然KRAS的突变是PDAC进展的早期启动事件，但大量证据证实了突变的KRAS对维持PDAC生长的重要性。制药业一直在努力开发突变KRAS功能的抑制剂，但到目前为止还没有抑制剂进入临床应用。因此，RAS效应器信号转导已成为药物发现的前沿。Raf-MEK-Erk丝裂原活化蛋白激酶通路是研究最多的典型RAS效应器，它包括三个非常容易处理的激酶。直到最近，Raf或MEK一直是唯一靶向的药物，在临床试验中，有18种抑制剂针对这两种成分。然而，当作为单一疗法使用时，它们在突变的RAS癌症中并未显示出有效性。这是由于从头机制和获得性耐药机制，导致ERK在抑制剂块下游重新激活，或通过使癌细胞对ERK依赖较少的机制。我推测，与Raf和MEK相比，直接抑制ERK将是一种更好的治疗方法。我的建议是基于我们的初步研究，评估了一种新型的ERK1和ERK2选择性蛋白激酶抑制剂(SCH77984；Merck)，它显示出比Raf或MEK抑制更有效的抗肿瘤活性。然而，我们也预计可能会出现耐药机制，导致从头开始或抑制剂选择的获得性耐药。使用从头开始耐药细胞，我们应用Kinome siRNA筛选，并确定了19个激酶，当抑制时，导致对SCH77984的敏感性增加5倍。这些代表了联合抑制剂治疗和SCH77984的候选靶点，以实现更有效的ERK靶向治疗。最后，由于K-RAS已知使用多个效应器来推动癌症的发展，我假设同时抑制其他效应器也可能增强SCH772984的抗肿瘤活性。我建议进行研究，以确定(1)ERK在PDAC生长、侵袭和转移中的作用，(2)对SCH772984从头耐药的机制，以及(3)同时抑制KRAS效应通路是否协同增强SCH772984的抗肿瘤活性。

DESCRIPTION (provided by applicant): Mutant KRAS is arguably the most significant therapeutic target for the treatment of pancreatic ductal adenocarcinoma (PDAC). PDAC is uniquely defined by an ~100% incidence of oncogenic mutations in KRAS. Though mutations in KRAS are any early initiating event in PDAC progression, substantial evidence validate the importance of mutant KRAS for maintenance of PDAC growth. There has been an intensive effort by the pharmaceutical industry to develop inhibitors of mutant KRAS function, but to date no inhibitors have reached clinical application. As a consequence, Ras effector signaling has moved to the forefront of drug discovery. The best-studied canonical Ras effector is the Raf-Mek-Erk mitogen-activated protein kinase pathway, which includes three very tractable kinases. Until recently, there has been an exclusive targeting of Raf or Mek, with 18 inhibitors targeting these two components in clinical trials. However, when used as monotherapy, they have not shown effectiveness in mutant Ras cancers. This is due to both de novo and acquired resistance mechanisms that lead to reactivation of Erk downstream of the inhibitor block or through mechanisms that render cancer cells less dependent on Erk. I hypothesize that direct inhibition of Erk will be a superior therapy compared to Raf and Mek. My proposal is based on our preliminary studies evaluating a novel Erk1 and Erk2 selective protein kinase inhibitor (SCH77984; Merck) that exhibits more effective anti-tumor activity than Raf or Mek inhibition. However, we also anticipate that resistance mechanisms can arise that cause de novo or inhibitor-selected acquired resistance. Using de novo resistant cells, we applied a kinome siRNA screen and identified 19 kinases that when suppressed caused a 5-fold enhanced sensitivity to SCH77984. These represent candidate targets for combination inhibitor treatment together with SCH77984 for more effective Erk-targeted therapies. Finally, because K-Ras is known to use multiple effectors to drive cancer development, I hypothesize that concurrent inhibition of other effectors may also enhance the anti-tumor activity of SCH772984. I propose studies to determine (1) the role of Erk in PDAC growth, invasion and metastasis, (2) mechanisms of de novo resistance to SCH772984, and finally, (3) whether concurrent suppression of KRAS effector pathways synergistically enhances SCH772984 anti-tumor activity.