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

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

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.
PMID: 36959380 DOI: 10.1038/s41416-023-02222-0
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.

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