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 and methods: An initial analysis of CDK/cyclin gene expression involved an American national biomarker database of deidentified patients (Caris Life Sciences, Phoenix, AZ; n = 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 = 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.