Targeting context-cpecific dependent transcriptional addiction in bone and soft tissue sarcoma: advance and future / 中华骨科杂志

ABSTRACT

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.