靶向调控转录依赖的关键因子在恶性骨肿瘤中的研究进展

Targeting context-cpecific dependent transcriptional addiction in bone and soft tissue sarcoma:advance and future

骨肿瘤高度的异质性使新型分子靶向疗法的发展受到一定局限,但另一方面也提示基因组多样性的共同表达调控通路可能为临床治疗提供至关重要的线索。相比点突变为主的癌,骨与软组织肉瘤在遗传学上以染色体改变为特征,产生的特异蛋白多是核心转录因子,驱动异常的转录调节进程,从而主导骨肿瘤的发生、发展。骨肿瘤恶性生物学行为的维持依赖转录的持续高水平活化,因此针对转录失调过程中关键的调控因子开发靶向药物可能是骨肿瘤治疗的前景方向。已证实细胞周期蛋白依赖性激酶-7(cyclin-dependent kinase-7,CDK7)是肿瘤异常转录调控的枢纽性节点,其通过磷酸化RNA聚合酶Ⅱ影响细胞生长、增殖、转移等多种生物学功能。关键因子CDK7的精细调控决定着肿瘤特征性的转录依赖,靶向抑制CDK7是阻遏肿瘤生长的有效策略,尤其是特定遗传背景的肿瘤类型对CDK7的干预高度敏感。越来越多的研究表明,CDK7与骨肿瘤的发生、发展密切相关,有望成为骨肿瘤治疗的潜力靶标。

High heterogeneity of bone and soft tissue sarcomas limits the development of molecular-targeted therapy but in turn provides an important clue to inner genomic and regulomic diversityof driver pathways that define molecular subtypes associated with patient outcome.The importance of malignant biological behaviorshave been re-emphasized,since tumor arises from the collaborative interplay of oncogenic events acquired the tissue-specifying gene expression programs to survive cancer cells and benefit multi-step tumorigenesis and neoplastic progression.Differ from most epithelial carcinomas that harbor clinically operative mutation sites,sarcomas are characterizedpredominantly by chromosomal alterations and copy-number changes,with low mutation loads.Sarcoma-specific fusion proteins produced by chromosomal translocations are common significant transcription factors,driving tumor cells exhibit an absolute dependence on"transcription addiction".It has been confirmed that cyclin-dependent kinase-7(CDK7)plays a key role in transcriptional regulation such as cell growth and proliferation,invasion and metastasis.The dysregulated transcriptional regulation acquired during tumor development strictly depends on the essential regulation of CDK7.Targeted inhibition of CDK7 is an effective strategy to suppress tumors,especially those with specific genomic backgrounds(oncogene or fusion-gene driven)which are highly sensitive to CDK7 intervention.Emerging studies have shown that CDK7 is closely related to the malignant behaviors of bone and soft tissue sarcomas,and is expected to become a potential target for the treatment of sarcoma.