Pansarcoma analysis of cyclin-dependent kinase and cyclin outlier gene expression highlights CDK7 as a potential therapeutic target in chordoma Journal Article
| Authors: | Lefler, D. S.; Elliott, A.; Jiang, W.; Martinez-Outschoorn, U.; Al-Sabah, J.; Freed, D. M.; King, C. M.; Maki, R. G.; Riedel, R. F.; Modiano, J. F.; Hübschmann, D.; Glimm, H.; Fröhling, S.; Oberley, M.; Boikos, S. A.; Mallick, A. B. |
| Article Title: | Pansarcoma analysis of cyclin-dependent kinase and cyclin outlier gene expression highlights CDK7 as a potential therapeutic target in chordoma |
| Abstract: | PURPOSE Cyclin-dependent kinase (CDK)4/6 inhibitors are approved for the treatment of breast cancer, and they have more recently been used in patients with well-differentiated/dedifferentiated liposarcomas (WD-LPSs/DD-LPSs). However, targeting of these and other CDKs, including transcriptional CDKs, remains a promising avenue of investigation for various cancers. Therefore, we sought to characterize outlier overexpression of CDK and cyclin genes in sarcomas. On the basis of the initial results, further studies were undertaken to investigate the roles of CDK7 and CDK18 in chordomas. MATERIALS An initial analysis of CDK/cyclin gene expression involved an American national AND METHODS biomarker database of deidentified patients (Caris Life Sciences, Phoenix, AZ; n 5 3,757) using novel, strict definitions to identify outlier overexpressing samples across subtypes. Results were validated with a German national database (Molecularly Aided Stratification for Tumor Eradication Research [MASTER]; n 5 943). Outlier overexpression for CDK7/18 in chordoma was compared with immunohistochemical (IHC) expression using tissue microarrays, and a selective investigational CDK7 inhibitor was tested against four chordoma cell lines. RESULTS Initial analysis identified expected findings (eg, outlier overexpression of CDK4 in 39%-66% of WD-LPSs/DD-LPSs), clinical correlates of fundamental scientific work (eg, CCND1 in 29% of Ewing sarcomas), and novel associations (eg, CDK7/CDK18 in 42%/37% of chordomas). Outlier overexpression for CDK7 and CDK18 in chordomas was corroborated in the MASTER database (40% and 26% of patients, respectively). IHC analysis confirmed strong and diffuse expression of both CDK7 and CDK18 in chordoma samples. Furthermore, CDK7 inhibition was highly effective in four chordoma cell lines. CONCLUSION This study supports further investigation into targeting of CDKs and cyclins in select sarcoma subtypes, and it specifically suggests a therapeutic approach inhibiting CDK7 in chordoma. © 2025 by American Society of Clinical Oncology. |
| Keywords: | immunohistochemistry; osteosarcoma; adult; controlled study; protein expression; unclassified drug; human cell; protein function; gene overexpression; gene expression; cyclin dependent kinase 8; genetic association; angiosarcoma; ewing sarcoma; sarcoma; fibrosarcoma; messenger rna; microarray analysis; follicular dendritic cell sarcoma; kaposi sarcoma; tissue microarray; cycline; leiomyosarcoma; malignant fibrous histiocytoma; rhabdomyosarcoma; solitary fibrous tumor; spindle cell sarcoma; synovial sarcoma; cyclin d1; cyclin dependent kinase; cyclin dependent kinase inhibitor; malignant peripheral nerve sheath tumor; dna extraction; chondrosarcoma; neuroectoderm tumor; chordoma; epithelioid sarcoma; genomic dna; embryonal rhabdomyosarcoma; cyclin e; liposarcoma; clear cell sarcoma; rna extraction; cyclin dependent kinase 4; desmoid tumor; alveolar soft part sarcoma; desmoplastic small round cell tumor; myxosarcoma; cyclin dependent kinase 7; endometrial stromal tumor; cyclin dependent kinase 6; cyclin d2; alveolar rhabdomyosarcoma; cyclin dependent kinase 2; perivascular epithelioid cell tumor; fibromyxosarcoma; plasma cell granuloma; cyclin a1; dedifferentiated liposarcoma; epithelioid hemangioendothelioma; cyclin b3; well differentiated liposarcoma; human; article; dedifferentiated chondrosarcoma; rna sequencing; pleomorphic rhabdomyosarcoma; angiomyxoma; whole transcriptome sequencing; cyclin dependent kinase 18; chondroblastic osteosarcoma; giant cell sarcoma |
| Journal Title: | JCO Precision Oncology |
| Volume: | 9 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2025-08-01 |
| Start Page: | e2500149 |
| Language: | English |
| DOI: | 10.1200/po-25-00149 |
| PUBMED: | 40601892 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
