Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 17, 2021
- Source ID
- 10.1158/2159-8290.cd-21-0702
Entities
People
- Aditya Bardia
- Avinash Kambadakone
- Brian P. Danysh
- Charlotte S. Walmsley
- Chaya Levovitz
- Daniel E. McLoughlin
- Dejan Juric
- Elizabeth E. Martin
- Elyssa Denault
- Filippo Utro
- Gad Getz
- Ignaty Leshchiner
- James R. Stone
- James T. Coates
- Kahn Rhrissorrakrai
- Kara Slowik
- Laxmi Parida
- Leif W Ellisen
- Nayana Thimmiah
- Raquel A. Jacobs
- Sheng Sun
- Steven J. Isakoff
Organizations
- Harvard University
- Massachusetts General Hospital
- National Institutes of Health
- United States Department of Defense