文章：

靶向RAS信号通路的癌症治疗

Targeting RAS signalling pathways in cancer therapy

原文发布日期：2003-01-01

DOI: 10.1038/nrc969

类型: Review Article

开放获取: 否

要点：

1. RAS proteins, their regulators and the downstream enzymes that they control are activated in many tumour types by a variety of mechanisms, including oncogenic mutation of RAS genes.
2. They are crucial mediators of several of the malignant characteristics of transformed cells and are therefore good candidates for tumour therapy.
3. RAS proteins require post-translational modification by farnesylation to be biologically active. Farnesyl transferase inhibitors have some antitumour activity in the clinic, but they seem to act through targets other than RAS.
4. Kinase inhibitors that block either RAF or mitogen-activated protein (MAP) kinase kinase MEK in the RAF/MAP kinase pathway downstream of RAS have been developed and show promise in early clinical trials.
5. Inhibitors acting on epidermal growth factor (EGF) receptor and ERBB2 upstream activators of RAS have been developed. Antibodies directed against ERBB2 have been licensed for the treatment of breast cancer, whereas small-molecule EGF receptor inhibitors show potential against lung cancer in clinical trials.
6. Other RAS-related therapies are in development, including inhibitors of AKT/PKB kinase activity, which is activated by RAS oncogenic mutation and by PTEN tumour-suppressor gene loss.

要点翻译：

1. RAS蛋白及其调节因子以及它们所控制的下游酶在许多肿瘤类型中通过多种机制被激活，包括RAS基因的致癌突变。
2. 它们是转化细胞多种恶性特征的关键介质，因此是肿瘤治疗的理想靶点。
3. RAS蛋白需要经过法尼基化翻译后修饰才能获得生物活性。法尼基转移酶抑制剂在临床上具有一定的抗肿瘤活性，但它们似乎通过RAS以外的靶点发挥作用。
4. 针对RAS下游RAF/MAP激酶通路中RAF或丝裂原活化蛋白（MAP）激酶激酶MEK的激酶抑制剂已被开发出来，并在早期临床试验中显示出前景。
5. 作用于RAS上游激活因子表皮生长因子（EGF）受体和ERBB2的抑制剂也已问世。针对ERBB2的抗体已获准用于乳腺癌治疗，而小分子EGF受体抑制剂在临床试验中显示出对抗肺癌的潜力。
6. 其他RAS相关疗法正在开发中，包括AKT/PKB激酶活性抑制剂——该激酶可通过RAS致癌突变和PTEN抑癌基因缺失被激活。

英文摘要：

The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. They are aberrant in most human tumours due to activating mutations in the RAS genes themselves or to alterations in upstream or downstream signalling components. Rational therapies that target the RAS pathways might inhibit tumour growth, survival and spread. Several of these new therapeutic agents are showing promise in the clinic and many more are being developed.

摘要翻译： 

胰腺导管腺癌是一种侵袭性强、破坏力大的疾病，其特征是侵袭性、快速进展和对治疗的深度抵抗。病理分类和癌症遗传学的进展提高了我们对该疾病的描述性理解；然而，胰腺癌生物学的重要方面仍知之甚少。特定基因突变的致病作用是什么？起源细胞是什么？基质如何促进肿瘤发生？对胰腺癌生物学的更好理解应为更有效的治疗开辟道路。

原文链接：

Targeting RAS signalling pathways in cancer therapy