HER2 Antibody-Drug Conjugates Are Active against Desmoplastic Small Round Cell Tumor.

Autor:	Zhang T; New York Medical College, Valhalla, New York.; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Febres-Aldana CA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Liu Z; Department of Pathology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Dix JM; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Cheng R; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Renaissance School of Medicine, Stony Brook University, Stony Brook, New York., Dematteo RG; Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, New York., Lui AJW; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Cancer Research UK, University of Cambridge, Cambridge, United Kingdom., Khodos I; Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Gili L; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Mattar MS; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Lisanti J; Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Kwong C; Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Linkov I; Pathology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York., Tipping MJ; Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York., de Stanchina E; Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Odintsov I; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Ladanyi M; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Somwar R; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Oct 15; Vol. 30 (20), pp. 4701-4713.
DOI:	10.1158/1078-0432.CCR-24-1835
Abstrakt:	Purpose: Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation, with very poor outcomes. Herein, we evaluated ERBB2/HER2 expression in DSRCT as a therapeutic target. Experimental Design: ERBB2/HER2 expression was assessed in clinical samples and patient-derived xenografts (PDX) using RNA sequencing, RT-qPCR, and a newly developed HER2 IHC assay (clone 29D8). Responses to HER2 antibody-drug conjugates (ADC)-trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine-were evaluated in DSRCT PDX, cell line, and organoid models. Drug internalization was demonstrated by live microscopy. Apoptosis was evaluated by Western blotting and caspase activity assays. Results: ERBB2/HER2 was detectable in DSRCT samples from patients and PDXs, with higher sensitivity RNA assays and improved IHC detectability using clone 29D8. Treatment of ERBB2/HER2-expressing DSRCT PDX, cell line, and organoid models with T-DXd or trastuzumab emtansine resulted in tumor regression. This therapeutic response was long-lasting in T-DXd-treated xenografts and was mediated by rapid HER2 ADC complex internalization and cytotoxicity, triggering p53-mediated apoptosis and growth arrest. Xenograft regression was associated with bystander payload effects triggering global tumor niche responses proportional to HER2 status. Conclusions: ERBB2/HER2 is a therapeutic target in DSRCT. HER2 ADCs may represent novel options for managing this exceptionally aggressive sarcoma, possibly fulfilling an urgent and historically unmet need for more effective clinical therapy. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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