Targeting ERK5 for Colorectal Cancer Therapy

摘要 在美国，大约有14万名患者被诊断为结直肠癌，死亡人数为5万人 每年。这些患者中几乎有一半有RAS或BRAF突变，而目前还没有 有效的治疗。活化的MAPK信号在结直肠癌的发病机制中起重要作用。药理作用 突变的BRAFV600E、MEK1/2和最近的ERK1/2的抑制剂已经被开发出来用于靶向治疗。 垂直靶向MAPK通路，特别是与表皮生长因子受体(EGFR)结合时 阻止其反馈激活的抑制剂，为结直肠癌的系统治疗带来了希望。然而，主要的 与黑色素瘤等其他癌症相比，对靶向治疗的抵抗是结直肠癌的主要障碍。 以及对治疗表现出获得性抗药性的肺癌。EGFR/RAF或RAF/MEK的组合 抑制剂已经在实验室和临床上进行了测试，最近一种三重抑制剂鸡尾酒(EGFR/RAF/MEK)已经 已经在BRAFV600E突变的CRC中进行了临床评估。然而，在所有研究中，残留的MAPK信号是 被确定为耐药的原因，患者应答率低。残存MAPK的作用机制 人们对信号的理解很少。我们在肠上皮细胞中发现了一种新的耐药机制 小鼠体内ERK1/2基因缺失及MEK对人结直肠癌细胞的影响 体外试验中的抑制剂。这种分子机制包括激活一个非典型的MAPK家族成员ERK5， 它为规范的MAPK信号通路提供了旁路信号通路。因此，假设 这项研究的基础是“ERK5的治疗靶点，特别是当RAS或BRAF 是癌症的驱动力，与其他靶向药物和/或化疗药物相结合将增强抑制作用 结直肠癌的增殖和转移。ERK5与EGFR、RAF和/或 MEK抑制剂将对具有致癌KRAS或BRAF突变的CRC患者特别有效，因为 这种方法防止通过平行途径获得抵抗力“。我们将进行的研究是：调查 大肠癌中ERK5上调的分子机制及ERK5作为转录激活因子的作用 KRAS突变患者来源的大肠癌样本中ERK5信号的评估； 靶向ERK5治疗耐MEK抑制剂的结直肠癌患者移植瘤的研究 探员们。这是一个探索性的发展研究项目，旨在获得临床前数据，以验证潜在的新的 临床靶点ERK5与肿瘤进展、血管生成和结直肠癌转移密切相关。这些信息 获得的结果将为ERK5抑制剂与EGFR/RAF/的联合临床试验提供基础 结直肠癌患者的MEK抑制剂鸡尾酒。

ABSTRACT Colorectal cancer (CRC) is diagnosed in about 140,000 patients in the US, with a mortality of 50,000 patients per year. Almost half of these patients have either a RAS or BRAF mutation for which there is currently no effective therapy. Activated MAPK signaling plays a major role in the pathogenesis of CRC. Pharmacological inhibitors of mutant BRAFV600E, MEK1/2, and more recently ERK1/2 have been developed for targeted therapy. Vertical targeting the MAPK pathway, particularly in combination with epidermal growth factor receptor (EGFR) inhibitors to prevent its feedback activation, holds promise for the systemic treatment of CRC. However, primary resistance to targeted therapy is a major obstacle in CRC, as compared with other cancers such as melanoma and lung cancer which exhibit acquired resistance to therapy. Combinations of EGFR/RAF or RAF/MEK inhibitors have been tested in the lab and clinic, and recently a triple inhibitor cocktail (EGFR/RAF/MEK) has been clinically evaluated in BRAFV600E mutant CRC. However, in all studies residual MAPK signaling was identified as a cause of resistance with low patient response rates. The mechanism of the residual MAPK signaling is poorly understood. We have found a novel resistance mechanism in intestinal epithelial cells upon genetic deletion of ERK1/2 in mice in vivo, as well as in response to treatment of human CRC cells with MEK inhibitors in vitro. This molecular mechanism involves activation of an atypical MAPK family member, ERK5, which provides a by-pass signaling pathway to the canonical MAPK signaling pathway. Thus, the hypothesis upon which the studies are based is that “therapeutic targeting of ERK5, particularly when either RAS or BRAF is the cancer driver, in combination with other targeted agents and/or chemotherapeutics will enhance inhibition of CRC proliferation and metastasis. Pharmacological targeting of ERK5 in combination with EGFR, RAF and/or MEK inhibitors will be particularly effective in CRC patients with oncogenic KRAS or BRAF mutations, as this approach prevents acquired resistance via parallel pathways”. The studies we will conduct are to: investigate the molecular mechanisms causing ERK5 upregulation in CRC and the role of ERK5 as a transcriptional activator of angiogenesis in CRC cells; evaluate of ERK5 signaling in patient-derived CRC samples with KRAS mutations; and an investigation of treatment of MEK inhibitor-resistant CRC patient derived xenografts with ERK5 targeted agents. This an exploratory developmental research project to obtain preclinical data validating a potential new clinical target, ERK5, responsible for tumor progression, angiogenesis and metastasis of CRC. The information obtained will provide the basis for a clinical trial of the combination of an ERK5 inhibitor, with an EGFR/RAF/ MEK inhibitor cocktail in CRC patients.