文章：

致癌酪氨酸激酶和DNA损伤反应

Oncogenic tyrosine kinases and the dna-damage response

原文发布日期：2002-05-01

DOI: 10.1038/nrc799

类型: Review Article

开放获取: 否

要点：

1. Mutation and overexpression of tyrosine kinases causes their constitutive activation, often leading to malignant transformation. These oncogenic tyrosine kinases (OTKs) can induce uncontrolled growth, protection from apoptosis, inhibition of differentiation and/or dysregulation of adhesion.
2. Chemotherapy and radiotherapy have been successfully used for several decades to treat cancer, but cures are still rare events in OTK-positive tumours, because OTKs can induce resistance to cytostatic drugs and irradiation by means of at least three mechanisms:
3. Following DNA damage, OTKs enhance repair of DNA lesions (especially by homologous recombination repair).
4. They also prolong activation of cell-cycle checkpoints, providing more time for repair of otherwise lethal lesions.
5. By upregulating anti-apoptotic members of the B-cell lymphoma (BCL2) family, such as BCL-X_L, OTKs provide a cytoplasmic 'umbrella', protecting mitochondria in a tumour cell from the 'rain' of apoptotic signals coming from the damaged DNA in the nucleus, thereby preventing release of cytochrome c and activation of caspases.
6. The unrepaired and aberrantly repaired DNA lesions that result from spontaneous and/or drug-induced damage can therefore accumulate in OTK-containing tumour cells, leading to genomic instability and malignant progression.
7. OTKs represent a good target for antitumour treatments. However, simultaneous treatment with OTK inhibitors and chemo- or radiotherapy might represent a more rational strategy, because OTK inhibitors should abrogate OTK-induced resistance to DNA damage and increase the efficiency of chemo-/radiotherapy. Such experimental strategies are in clinical trials.

要点翻译：

1. 酪氨酸激酶的突变和过度表达导致其持续性激活，常引发恶性转化。这些致癌性酪氨酸激酶（OTKs）可诱导不受控的生长、凋亡逃逸、分化抑制和/或细胞黏附失调。
2. 化疗与放疗虽已成功应用于癌症治疗数十年，但在OTK阳性肿瘤中治愈仍属罕见。这是因为OTKs通过至少三种机制诱导对细胞抑制药物和放射治疗的耐药性：
3. DNA损伤后，OTKs增强DNA损伤修复（尤其通过同源重组修复途径）；
4. 延长细胞周期检查点的激活时间，为修复致命损伤提供更长时间；
5. 通过上调B细胞淋巴瘤2（BCL2）家族抗凋亡成员（如BCL-XL），OTKs形成细胞质"保护伞"，使肿瘤细胞线粒体免受细胞核内损伤DNA所产生的凋亡信号"冲击"，从而抑制细胞色素c释放和半胱天冬酶激活。
6. 因此，自发性和/或药物诱导损伤产生的未修复及异常修复的DNA损伤可在OTK阳性肿瘤细胞中累积，导致基因组不稳定性和恶性进展。
7. OTKs是抗肿瘤治疗的理想靶点。然而，联合使用OTK抑制剂与化疗或放疗可能是更合理的策略——因为OTK抑制剂能消除OTK诱导的DNA损伤耐药性，并提高放化疗效率。此类实验性策略目前已进入临床试验阶段。

英文摘要：

Oncogenic tyrosine kinases (OTKs) are involved in the induction of many types of tumour, including haematological malignancies and cancers of the breast, prostate, colon and lung. Neoplastic cells that express OTKs are usually resistant to apoptosis that is induced by DNA-damaging agents, such as cytostatic drugs and irradiation, and they display genomic instability. So, what are the mechanisms involved, and what is the potential for overcoming OTK-mediated resistance in the clinic?

摘要翻译： 

致癌性酪氨酸激酶（OTKs）参与诱导多种肿瘤，包括血液系统恶性肿瘤以及乳腺癌、前列腺癌、结肠癌和肺癌。表达OTKs的肿瘤细胞通常对由DNA损伤剂（如细胞毒药物和放射）诱导的凋亡具有抗性，并表现出基因组不稳定性。那么，其机制是什么？在临床上克服OTK介导的耐药性又有哪些潜在策略？

原文链接：

Oncogenic tyrosine kinases and the dna-damage response