Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer.
James Coates,Sheng Sun,Ignaty Leshchiner,Nayana Thimmiah,Elizabeth E. Martin,Daniel E. McLoughlin,Brian P. Danysh,Kara Slowik,Raquel A. Jacobs,Kahn Rhrissorrakrai,Filippo Utro,Chaya Levovitz,Elyssa Denault,Charlotte S. Walmsley,Avinash Kambadakone,James R. Stone,Steven J. Isakoff,Laxmi Parida,Dejan Juric,Gad Getz,Aditya Bardia,Leif W. Ellisen +21 more
TLDR
In this article, the authors identify mechanisms of SG resistance through RNA and whole-exome sequencing of pretreatment and post-progression specimens, highlighting the specificity of SG and illustrates how such mechanisms will inform therapeutic strategies to overcome ADC resistance.Abstract:
Sacituzumab govitecan (SG), the first antibody–drug conjugate (ADC) approved for triple-negative breast cancer, incorporates the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload. We sought to identify mechanisms of SG resistance through RNA and whole-exome sequencing of pretreatment and postprogression specimens. One patient exhibiting de novo progression lacked TROP2 expression, in contrast to robust TROP2 expression and focal genomic amplification of TACSTD2/TROP2 observed in a patient with a deep, prolonged response to SG. Analysis of acquired genomic resistance in this case revealed one phylogenetic branch harboring a canonical TOP1E418K resistance mutation and subsequent frameshift TOP1 mutation, whereas a distinct branch exhibited a novel TACSTD2/TROP2T256R missense mutation. Reconstitution experiments demonstrated that TROP2T256R confers SG resistance via defective plasma membrane localization and reduced cell-surface binding by hRS7. These findings highlight parallel genomic alterations in both antibody and payload targets associated with resistance to SG. Significance: These findings underscore TROP2 as a response determinant and reveal acquired SG resistance mechanisms involving the direct antibody and drug payload targets in distinct metastatic subclones of an individual patient. This study highlights the specificity of SG and illustrates how such mechanisms will inform therapeutic strategies to overcome ADC resistance. This article is highlighted in the In This Issue feature, p. 2355read more
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TROP2 Expression Across Molecular Subtypes of Urothelial Carcinoma and Enfortumab Vedotin-resistant Cells.
Jonathan Chou,Kai Trepka,Martin Sjöström,Emily A. Egusa,Carissa Chu,Jun Zhu,Emily Chan,Ewan A. Gibb,M. Badura,Alberto Contreras-Sanz,Bradley A. Stohr,Maxwell V. Meng,Raj S. Pruthi,Yair Lotan,Peter C. Black,Sima P. Porten,Vadim S. Koshkin,Terence W. Friedlander,Felix Y. Feng +18 more
TL;DR: In this article , the authors investigated the expression levels of the drug target TROP2 across different molecular subtypes of bladder cancer in multiple patient cohorts and cell lines and found that SG may be effective across most bladder cancer subtypes including the bladder cancers previously treated with enfortumab vedotin (EV) exposure.
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TL;DR: In this paper , the authors discuss the mechanisms of resistance to different HER2-targeted therapies, including monoclonal antibodies, small tyrosine kinase inhibitors, and antibody-drug conjugates.
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