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: 8598370
• 负责人: Tikvah K Hayes
• 金额: $ 2.62万
• 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 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598370
• 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; 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）的最重要的治疗靶标。 PDAC是由KRAS中致癌突变发生率约100％的唯一定义的。尽管KRAS中的突变是PDAC进展的任何早期启动事件，但大量证据证明了突变体KRAS在维持PDAC增长方面的重要性。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，尚无抑制剂达到临床应用。结果，RAS效应子信号已移至药物发现的最前沿。研究最佳的规范RAS效应器是RAF-MEK-ERK促分裂原激活的蛋白激酶途径，其中包括三种非常可拖动的激酶。直到最近，皇家空军或MEK的独家靶向，有18个抑制剂针对临床试验中的这两个组成部分。但是，当用作单一疗法时，它们在突变的RAS癌中尚未显示出有效性。这是由于从头开始和获得的耐药机制引起的，这些机制导致抑制剂阻滞下游的ERK或通过使癌细胞较少依赖ERK的机制重新激活。我假设与RAF和MEK相比，直接抑制ERK将是一种优越的疗法。我的建议基于我们评估新型ERK1和ERK2选择性蛋白激酶抑制剂（SCH77984; Merck）的初步研究，该研究表现出比RAF或MEK抑制更有效的抗肿瘤活性。但是，我们还预计会产生抗药性机制，从而导致从头或抑制剂选择的获得性抗性。使用从头耐药细胞，我们应用了一个Kinome siRNA筛选，并确定了19种激酶，当抑制引起5倍对SCH77984的敏感性时。这些代表了与SCH77984一起进行组合抑制剂治疗的候选靶标，以实现更有效的ERK靶向疗法。最后，由于已知K-RAS使用多个效应子来驱动癌症的发展，因此我假设同时抑制其他效应子也可能增强SCH772984的抗肿瘤活性。我提出的研究确定（1）ERK在PDAC生长，侵袭和转移中的作用，（2）对SCH772984的从头耐药性的机制，最后（3）（3）（3）是否同时抑制Kras效应途径的同时抑制会增强SCH772984抗肿瘤活性。