Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma PMID: 36959380

ADC Targets in Oncology

2026-04-10

Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma

Br J Cancer. 2023 Mar 23. doi: 10.1038/s41416-023-02222-0.

Samuel V Rasmussen ^# ¹ , Agnieszka Wozniak ^# ² , Melvin Lathara ³ , Joshua M Goldenberg ⁴ , Benjamin M Samudio ⁴ , Lissett R Bickford ¹ , Kiyo Nagamori ¹ , Hollis Wright ³ , Andrew D Woods ¹ , Shefali Chauhan ¹ , Che-Jui Lee ² , Erin R Rudzinski ⁵ , Michael K Swift ¹ , Tadashi Kondo ⁶ , David E Fisher ⁷ , Evgeny Imyanitov ⁸ , Isidro Machado ⁹ , Antonio Llombart-Bosch ¹⁰ , Irene L Andrulis ¹¹ ¹² , Nalan Gokgoz ¹¹ , Jay Wunder ¹¹ ¹³ ¹⁴ , Hiroshi Mirotaki ¹⁵ , Takuro Nakamura ¹⁶ , Ganapati Srinivasa ³ , Khin Thway ¹⁷ , Robin L Jones ¹⁸ , Paul H Huang ¹⁹ , Noah E Berlow ^# ²⁰ , Patrick Schöffski ^# ² , Charles Keller ^# ²¹

Affiliations

1. Children's Cancer Therapy Development Institute, Beaverton, OR, USA.
2. University Hospitals Leuven, Department of General Medical Oncology, and Laboratory of Experimental Oncology, KU Leuven, Leuven Cancer Institute, Leuven, Belgium.
3. Omics Data Automation, Beaverton, OR, USA.
4. Atomwise Inc, San Francisco, CA, USA.
5. Department of Pathology, Seattle Children's Hospital, Seattle, WA, USA.
6. Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan.
7. Department of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
8. N.N. Petrov National Medicine Research Center of Oncology, St. Petersburg, Russia.
9. Pathology Department, Instituto Valenciano de Oncología and Patologika Laboratorio, Hospital QuironSalud, Valencia, Spain.
10. Pathology Department, University of Valencia, Valencia, Spain.
11. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
12. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
13. University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, ON, Canada.
14. Division of Orthopaedic Surgery, Department of Surgery, University of Toronto, Toronto, Canada.
15. Division of Pediatrics, University of Miyazaki, Miyazaki, Japan.
16. The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
17. Sarcoma Unit, Royal Marsden Hospital, Division of Molecular Pathology, Institute of Cancer Research, London, UK.
18. Sarcoma Unit, Royal Marsden Hospital, Division of Clinical Studies, Institute of Cancer Research, London, UK.
19. Sarcoma Unit, Royal Marsden Hospital, Division of Molecular Pathology, Institute of Cancer Research, London, UK. [email protected].
20. Children's Cancer Therapy Development Institute, Beaverton, OR, USA. [email protected].
21. Children's Cancer Therapy Development Institute, Beaverton, OR, USA. [email protected].
# Contributed equally.

Abstract

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.