Targeting K-Ras effector signaling for pancreatic cancer treatment

描述（由申请方提供）：突变型KRAS可以说是治疗胰腺导管腺癌（PDAC）的最重要治疗靶点。PDAC的唯一定义是KRAS中致癌突变的发生率约为100%。尽管KRAS突变是PDAC进展中的任何早期起始事件，但大量证据证实了突变KRAS对于维持PDAC生长的重要性。制药工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效应物信号传导已经移动到药物发现的最前沿。研究最多的经典Ras效应子是Raf-Mek-Erk促分裂原活化蛋白激酶途径，其包括三种非常易处理的激酶。直到最近，Raf或Mek一直是唯一的靶向药物，在临床试验中有18种抑制剂靶向这两种成分。然而，当作为单一疗法使用时，它们在突变型Ras癌症中没有显示出有效性。这是由于从头和获得性耐药机制导致抑制剂阻断下游的Erk重新激活或通过使癌细胞对Erk依赖性降低的机制。我假设直接抑制Erk将是一种比Raf和Mek更优越的上级疗法。我的建议是基于我们的初步研究评估一种新的Erk 1和Erk 2选择性蛋白激酶抑制剂（SCH 77984;默克），表现出更有效的抗肿瘤活性比Raf或Mek抑制。然而，我们也预计，耐药机制可能会出现，导致从头或邻居选择性获得性耐药。使用从头抗性细胞，我们应用激酶组siRNA筛选并鉴定了19种激酶，当抑制时，其对SCH 77984的敏感性增加5倍。这些代表了联合抑制剂治疗与SCH 77984更有效的ERK靶向治疗的候选目标。最后，由于已知K-Ras使用多种效应子来驱动癌症发展，因此我假设同时抑制其他效应子也可能增强SCH 772984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）SCH 772984的从头耐药机制，以及最后，（3）同时抑制KRAS效应通路是否协同增强SCH 772984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.