The DNA repair pathway as a therapeutic target to synergize with trastuzumab deruxtecan in HER2-targeted antibody–drug conjugate–resistant HER2-overexpressing breast cancer

• Published in: Journal of experimental & clinical cancer research Vol. 43; no. 1; pp. 236 - 20
• Main Authors: Lee, Jangsoon, Kida, Kumiko, Koh, Jiwon, Liu, Huey, Manyam, Ganiraju C., Gi, Young Jin, Rampa, Dileep R., Multani, Asha S., Wang, Jing, Jayachandran, Gitanjali, Lee, Dae-Won, Reuben, James M., Sahin, Aysegul, Huo, Lei, Tripathy, Debu, Im, Seock-Ah, Ueno, Naoto T.
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21.08.2024; BioMed Central; BMC
• Subjects: Analysis; Animals; Antibodies; Antimitotic agents; Antineoplastic agents; Biopharmaceutics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Camptothecin - therapeutic use; Cell death; Cell growth; Cell Line, Tumor; Chemotherapy; Development and progression; DNA; DNA damage; DNA damage repair pathway; DNA Repair; DNA sequencing; Drug Resistance, Neoplasm; Drug Synergism; Epigenetic inheritance; Female; Genes; Genomes; Genomics; Health aspects; HER2 antibody–drug conjugates; HER2+ breast cancer; HER2-directed ADC resistance; Humans; Immunoconjugates - pharmacology; Immunoconjugates - therapeutic use; Kinases; Medical research; Medicine, Experimental; Metastasis; Mice; Monoclonal antibodies; Nucleotide sequencing; Patients; Receptor, ErbB-2 - metabolism; RNA; T-DXd; Targeted cancer therapy; Trastuzumab - pharmacology; Trastuzumab - therapeutic use; Viral antibodies; Whole genome sequencing; Xenograft Model Antitumor Assays; United States > US; Japan; HER2+ breast cancer; T-DXd; HER2 antibody–drug conjugates; HER2-directed ADC resistance; DNA damage repair pathway
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-024-03143-3

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. 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. 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. 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.