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有望为结直肠癌的系统治疗带来希望。然而，主要的 或对靶向治疗的获得性抵抗是一个主要障碍，特别是在结直肠癌中，与其他 黑色素瘤和肺癌等癌症。EGFR/RAF或RAF/MEK抑制剂的组合 在实验室和临床上进行了测试，最近已经对三重抑制剂鸡尾酒(EGFR/RAF/MEK)进行了临床评估 在BRAFV600E突变体CRC中。然而，在所有研究中，MAPK信号的重新激活被确定为原因 耐药性和患者应答率低。MAPK信号的再激活机制较差 明白了。我们在肠上皮细胞中发现了一种新的耐药机制，即基因缺失 在小鼠体内的ERK1/2，以及在体外对MEK抑制剂处理人CRC细胞的反应。这 分子机制涉及到一个非典型的MAPK家族成员ERK5的激活，它提供了一个旁路 信号通路到典型的MAPK信号通路。因此，这些研究所依据的假设 以ERK5为治疗靶点，特别是当RAS或BRAF是癌症的驱动因素时， 与其他靶向药物和/或化疗药物联合使用将加强对结直肠癌增殖的抑制 和转移。ERK5与EGFR、RAF和/或MEK抑制剂联合的药理学靶向将 对于具有致癌的KRAS或BRAF突变的CRC患者尤其有效，因为这种方法防止了 通过平行途径获得抗药性“。我们将进行的研究是：研究分子 导致结直肠癌细胞ERK5上调的机制；患者来源的结直肠癌中ERK5信号的评估 KRAS突变的样本；以及一项对MEK抑制剂耐药的结直肠癌患者的治疗研究 ERK5靶向药物的异种移植。这是一个探索性的发展研究项目，旨在获得临床前研究 数据验证潜在的临床新靶点ERK5，与肿瘤的进展、侵袭和转移有关 中国铁路局的。所获得的信息将为ERK5抑制剂组合的临床试验提供基础， 联合应用EGFR/RAF/MEK抑制剂鸡尾酒治疗结直肠癌。

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 or acquired resistance to targeted therapy is a major obstacle, particularly in CRC as compared with other cancers such as melanoma and lung cancer. 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 the studies reactivation of MAPK signaling was identified as a cause of resistance and low patient response rates. The mechanism of the reactivation of 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 mechanism causing ERK5 upregulation 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, invasion 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.