Dana-Farber Researchers Identify CDK8 as a Potential Therapeutic Target for Alveolar Rhabdomyosarcoma

Research Summary

Study Title: CDK8 Inhibition Releases the Muscle Differentiation Block in Fusion-driven Alveolar Rhabdomyosarcoma

Publication: Cancer Discovery

Corresponding Dana-Farber Cancer Institute authors: Susu Zhang, PhD; Kimberly Stegmaier, MD

Summary: Dana-Farber Cancer Institute researchers studied alveolar rhabdomyosarcoma (aRMS), an aggressive childhood cancer with poor survival and few targeted treatment options, to identify new treatment vulnerabilities. Using a network-based analysis of large functional genomic datasets, they found that aRMS cells depend on CDK8, a protein involved in controlling gene activity.

The researchers then showed that blocking CDK8, either by gene knockout or with a drug, slowed tumor cell growth and caused the cancer cells to activate genes linked to normal skeletal muscle development. This suggests that CDK8 helps keep aRMS cells trapped in an immature, cancer-like state, and that inhibiting it can push them toward a more normal muscle cell identity. These effects were seen both in cell models and in animal studies.

The study also found that the drug’s full anti-tumor effect depends on other gene-regulating partners, including the Mediator kinase module, the SAGA complex, and the transcription factor SIX4, which appears to help switch on the muscle differentiation program. Together, the findings identify CDK8 as a promising therapeutic target and suggest that CDK8 inhibition could be a new differentiation-based treatment strategy for aRMS.

Significance: Alveolar rhabdomyosarcoma remains a hard-to-treat childhood cancer with limited targeted therapies and poor outcomes for many patients. This study identifies CDK8 as a promising new drug target and suggests that blocking it may impair tumor growth not only by slowing cancer cell proliferation, but also by driving the cells to restart a normal muscle development program.

The findings also show that this response depends on a broader network of gene-regulating proteins, including the Mediator kinase module, the SAGA complex, and SIX4. By clarifying how CDK8 inhibition works, the study provides strong rationale for further testing of CDK8 inhibitors, including in combination with existing treatments, as a potential new therapeutic approach for patients with aRMS.

Funding: National Cancer Institute R35 CA283977 (K.S.), U54 CA231630 (C.M.C, C.M.L., K.C.W.); UM1 CA294108 (C.M.L.); the CureSearch for Children’s Cancer Foundation, Hyundai Hope on Wheels, the Rally Foundation for Childhood Cancer Research, and the St. Baldrick’s Foundation (C.M.L.); the Palumbo Rhabdomyosarcoma Research Fund, and the Corinne Cecilia Sciarappa Fund. S.Z. is supported by an Alex’s Lemonade Stand Fellowship (#22-27271). CFM was supported by the National Institutes of Health under a Ruth L. Kirschstein National Research Service Award (F32CA243266). M.J. and B.G. were supported by NCI T32HD094671 Fellowships. This work was also supported by the Pediatric Cancer Dependencies Accelerator of the Broad Institute, Dana-Farber Cancer Institute, and St. Jude Children’s Research Hospital: pdedep.org.