Targeting K-Ras effector signaling for pancreatic cancer treatment

描述（由申请人提供）：突变KRAS可以说是治疗胰腺导管腺癌（PDAC）最重要的治疗靶点。PDAC的独特定义是KRAS中约100%的致癌突变发生率。尽管KRAS突变是PDAC进展中的任何早期启动事件，但大量证据证实了突变KRAS对维持PDAC生长的重要性。制药行业一直在努力开发突变KRAS功能的抑制剂，但迄今为止还没有抑制剂达到临床应用。因此，Ras效应信号已经走到了药物发现的前沿。研究得最好的典型Ras效应物是Raf-Mek-Erk丝裂原激活蛋白激酶途径，它包括三种非常容易处理的激酶。直到最近，在临床试验中，已有18种抑制剂靶向Raf或Mek这两种成分。然而，当作为单一疗法使用时，它们在突变的Ras癌症中没有显示出有效性。这是由于新生和获得性耐药机制导致抑制剂阻断下游Erk的再激活，或者通过使癌细胞减少对Erk的依赖的机制。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。我的提议是基于我们对一种新型Erk1和Erk2选择性蛋白激酶抑制剂（SCH77984; Merck）的初步研究，该抑制剂比Raf或Mek抑制剂具有更有效的抗肿瘤活性。然而，我们也预计耐药机制可能会引起新生或抑制剂选择获得性耐药。使用新生耐药细胞，我们应用了kinome siRNA筛选，并鉴定出19种激酶，当抑制时导致对SCH77984的敏感性提高5倍。这些代表了联合抑制剂与SCH77984治疗更有效的erk靶向治疗的候选靶点。最后，由于已知K-Ras使用多种效应物来驱动癌症发展，我假设同时抑制其他效应物也可能增强SCH772984的抗肿瘤活性。我建议研究确定(1)Erk在PDAC生长、侵袭和转移中的作用，(2)SCH772984从头耐药的机制，最后(3)同时抑制KRAS效应通路是否协同增强SCH772984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.