Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Outcomes for metastatic osteosarcoma (OS) remain poor despite treatment advances.
• There is a critical need for novel therapeutic strategies targeting OS metastasis.

Purpose of the Study:

• To develop a preclinical model for screening anti-metastatic compounds in OS.
• To identify novel therapeutic targets for osteosarcoma lung metastasis.

Main Methods:

• Developed a system for preclinical screening of compounds against metastatic OS cells within the lung microenvironment.
• Screened epigenetically targeted compounds, focusing on CDK12 inhibitors.
• Utilized in vivo models to assess the efficacy of CDK12 inhibition on OS lung colonization.

Main Results:

• CDK12 inhibitors reduced OS cell outgrowth in the lung by over 90% at submicromolar doses.
• CDK12 knockout significantly decreased OS lung colonization in vivo.
• CDK12 inhibition caused transcriptional defects, RNA processing issues, and altered DNA damage response gene expression.
• Identified differential sensitivity to CDK12 inhibition, potentially mediated by MYC levels.

Conclusions:

• CDK12 is a promising therapeutic target for osteosarcoma lung metastasis.
• The developed preclinical system facilitates rapid testing of anti-metastatic compounds.
• Further investigation into MYC's role in CDK12 inhibitor sensitivity is warranted.