Faculty, Staff and Student Publications
Publication Date
8-21-2024
Journal
Journal of Experimental Medicine
DOI
10.1186/s13046-024-03143-3
PMID
39164784
PMCID
PMC11337831
PubMedCentral® Posted Date
8-21-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Anti-HER2 therapies, including the HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2-based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo.
Methods: Targeted DNA and whole transcriptome sequencing were performed in breast cancer patient tissue samples to investigate genetic aberrations that arose after anti-HER2 therapy. We generated T-DM1 and T-DXd-resistant HER2+ breast cancer cell lines. To elucidate their resistance mechanisms and to identify potential synergistic kinase targets for enhancing the efficacy of T-DXd, we used fluorescence in situ hybridization, droplet digital PCR, Western blotting, whole-genome sequencing, cDNA microarray, and synthetic lethal kinome RNA interference screening. In addition, cell viability, colony formation, and xenograft assays were used to determine the synergistic antitumor effect of T-DXd combinations.
Results: We found reduced HER2 expression in patients and amplified DNA repair-related genes in patients after anti-HER2 therapy. Reduced ERBB2 gene amplification in HER2-directed ADC-resistant HER2+ breast cancer cell lines was through DNA damage and epigenetic mechanisms. In HER2-directed ADC-resistant HER2+ breast cancer cell lines, our non-biased RNA interference screening identified the DNA repair pathway as a potential target within the canonical pathways to enhance the efficacy of T-DXd. We validated that the combination of T-DXd with ataxia telangiectasia and Rad3-related inhibitor, elimusertib, led to significant breast cancer cell death in vitro (P < 0.01) and in vivo (P < 0.01) compared to single agents.
Conclusions: The DNA repair pathways contribute to HER2-directed ADC resistance. Our data justify exploring the combination treatment of T-DXd with DNA repair-targeting drugs to treat HER2-directed ADC-resistant HER2+ breast cancer in clinical trials.
Keywords
Humans, Female, Breast Neoplasms, Trastuzumab, DNA Repair, Animals, Immunoconjugates, Mice, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Cell Line, Tumor, Xenograft Model Antitumor Assays, Camptothecin, Drug Synergism, HER2+ breast cancer, HER2 antibody–drug conjugates, DNA damage repair pathway, T-DXd, HER2-directed ADC resistance
Published Open-Access
yes
Recommended Citation
Lee, Jangsoon; Kida, Kumiko; Koh, Jiwon; et al., "The DNA Repair Pathway as a Therapeutic Target to Synergize With Trastuzumab Deruxtecan in HER2-Targeted Antibody-Drug Conjugate-Resistant HER2-Overexpressing Breast Cancer" (2024). Faculty, Staff and Student Publications. 6634.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6634
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