Targeting K-Ras effector signaling for pancreatic cancer treatment

靶向 K-Ras 效应信号传导用于胰腺癌治疗

• 批准号: 8753070
• 负责人: Tikvah K Hayes
• 金额: $ 2.71万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8753070
• 关键词: Adenocarcinoma Cell; Anchorage-Independent Growth; Apoptosis; BRAF gene; Biological Assay; Bypass; Cancer Etiology; Cancer Model; Cell Cycle Progression; Cell Line; Cells; Cessation of life; Clinical Trials; Coin; Development; Disease; Drug Industry; Effectiveness; Event; Exhibits; FDA approved; Growth; In Vitro; Incidence; KRAS2 gene; Lead; Libraries; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Melanoma Cell; Methods; Mitogen-Activated Protein Kinases; Mutate; Mutation; Neoplasm Metastasis; Oncogene Proteins; Oncogenic; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phase; Phosphotransferases; Plastics; Protein Kinase; Protein Kinase Inhibitors; Protein Tyrosine Kinase; Regulation; Resistance; Role; Signal Transduction; Small Interfering RNA; Testing; Therapeutic; addiction; base; cancer cell; cancer therapy; clinical application; drug discovery; in vivo; inhibitor/antagonist; melanoma; mortality; mouse model; mutant; novel; novel strategies; pancreas xenograft; protein kinase inhibitor; public health relevance; research clinical testing; resistance mechanism; senescence; success; targeted treatment; therapeutic target; tumor; tumorigenic

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.

描述（由申请人提供）：突变体 KRAS 可以说是治疗胰腺导管腺癌 (PDAC) 的最重要的治疗靶点。 PDAC 的独特定义是 KRAS 中致癌突变的发生率约为 100%。尽管 KRAS 突变是 PDAC 进展的任何早期起始事件，但大量证据证实突变 KRAS 对于维持 PDAC 生长的重要性。制药行业一直致力于开发突变型 KRAS 功能的抑制剂，但迄今为止还没有任何抑制剂达到临床应用。因此，Ras 效应器信号转导已成为药物发现的前沿。研究最充分的典型 Ras 效应器是 Raf-Mek-Erk 丝裂原激活蛋白激酶途径，其中包括三种非常容易处理的激酶。直到最近，还有专门针对 Raf 或 Mek 的抑制剂，有 18 种针对这两种成分的抑制剂正在临床试验中。然而，当用作单一疗法时，它们尚未显示出对突变 Ras 癌症的有效性。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，或者通过使癌细胞减少对 Erk 依赖的机制。我假设与 Raf 和 Mek 相比，直接抑制 Erk 将是一种更好的疗法。我的建议基于我们对一种新型 Erk1 和 Erk2 选择性蛋白激酶抑制剂（SCH77984；默克）的初步研究，该抑制剂比 Raf 或 Mek 抑制剂表现出更有效的抗肿瘤活性。然而，我们还预计可能会出现耐药机制，导致从头或抑制剂选择的获得性耐药。使用从头耐药细胞，我们应用了激酶组 siRNA 筛选并鉴定了 19 种激酶，这些激酶在被抑制时会导致 SCH77984 的敏感性提高 5 倍。这些代表了联合抑制剂治疗与 SCH77984 的候选靶点，以实现更有效的 Erk 靶向治疗。最后，由于已知 K-Ras 使用多个效应器来驱动癌症发展，因此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）SCH772984 的从头耐药机制，最后，（3）同时抑制 KRAS 效应通路是否能协同增强 SCH772984 的抗肿瘤作用活动。