Related Experiment Video
Updated: Aug 5, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear
Samuel V Rasmussen1, Agnieszka Wozniak2, Melvin Lathara3
1Children's Cancer Therapy Development Institute, Beaverton, OR, USA.
Background:
Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults.
Methods:
To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines.
Results:
Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability.
Conclusion:
These studies of the genomic, transcriptomic and chemical biology landscape represent a resource 'atlas' for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCS is found.
Insights
Systemic therapy for clear cell sarcoma (CCS) is lacking. This study identified vulnerabilities, finding CHK inhibitors may be relevant and HER3 antibody-drug conjugates show potential for treating this rare cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Metastatic clear cell sarcoma (CCS) in pediatric and young adult patients lacks effective systemic therapies.
- EWSR1-CREB1/ATF1 fusions are characteristic of CCS, highlighting a need for targeted treatment strategies.
Purpose of the Study:
- To identify key signaling pathway vulnerabilities in clear cell sarcoma (CCS).
- To explore potential therapeutic targets for CCS through genomic, transcriptomic, and chemical biology approaches.
Main Methods:
- Conducted whole exome and RNA deep sequencing on 47 patient tumor samples and 8 cell lines.
- Performed integrated chemical biology interrogations, including inhibitor development and antibody-drug conjugate (ADC) testing.
Main Results:
- Identified recurrent mutations in cell cycle checkpoint and DNA repair genes.
- Observed DNA multi-copy gains with high RNA expression in subsets of CCS tumors.
- Demonstrated dose-dependent in vitro response of CCS cell lines to the HER3 ADC patritumab deruxtecan.
Conclusions:
- Established that CCS is not dependent on CREB1 activity, ruling out CREB1 inhibitors as a therapeutic strategy.
- Identified CHK inhibitors as potentially relevant for CCS treatment.
- Highlighted the potential utility of HER3 ADCs in the management of clear cell sarcoma.
