HER2 antibody-drug conjugates are active against desmoplastic small round cell tumor Journal Article
| Authors: | Zhang, T.; Febres-Aldana, C. A.; Liu, Z.; Dix, J. M.; Cheng, R.; Dematteo, R. G.; Lui, A. J. W.; Khodos, I.; Gili, L.; Mattar, M. S.; Lisanti, J.; Kwong, C.; Linkov, I.; Tipping, M. J.; de Stanchina, E.; Odintsov, I.; Ladanyi, M.; Somwar, R. |
| Article Title: | HER2 antibody-drug conjugates are active against desmoplastic small round cell tumor |
| Abstract: | 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. |
| Keywords: | genetics; mouse; animal; metabolism; animals; mice; apoptosis; epidermal growth factor receptor 2; camptothecin; drug effect; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; tumor cell line; receptor, erbb-2; drug therapy; trastuzumab; desmoplastic small round cell tumor; erbb2 protein, human; antibody conjugate; immunoconjugates; trastuzumab emtansine; humans; human; male; female; ado-trastuzumab emtansine; trastuzumab deruxtecan |
| Journal Title: | Clinical Cancer Research |
| Volume: | 30 |
| Issue: | 20 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-10-15 |
| Start Page: | 4701 |
| End Page: | 4713 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-24-1835 |
| PUBMED: | 39120576 |
| PROVIDER: | scopus |
| PMCID: | PMC11479846 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Marc Ladanyi -- Source: Scopus |
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