Patritumab deruxtecan (HER3-DXd), a novel HER3 directed antibody drug conjugate, exhibits in vitro activity against breast cancer cells expressing HER3 mutations with and without HER2 overexpression

• Published in: PloS one 2022-05, Vol.17 (5), p.e0267027-e0267027
• Main Authors: Koyama, Kumiko, Ishikawa, Hirokazu, Abe, Manabu, Shiose, Yoshinobu, Ueno, Suguru, Qiu, Yang, Nakamaru, Kenji, Murakami, Masato
• Format: Article
• Language: English
• Subjects: Antibodies; Antibodies, Monoclonal, Humanized; Anticancer properties; Antitumor activity; Biology and Life Sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Camptothecin - analogs & derivatives; Cancer therapies; Cell Line, Tumor; Cell proliferation; Cell surface; Cell survival; Colorectal cancer; Conjugates; ErbB-2 protein; ErbB-3 protein; Evaluation; Female; Flow cytometry; Gastric cancer; Humans; Immunoconjugates - therapeutic use; Kinases; Medicine and Health Sciences; Metastasis; Mutants; Mutation; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptor, ErbB-3 - metabolism; Research and Analysis Methods; Therapeutic targets; Trastuzumab - genetics; Trastuzumab - pharmacology; Triple Negative Breast Neoplasms - drug therapy; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0267027

ErbB3 (HER3), a member of the HER family, is overexpressed in various cancers and plays an important role in cell proliferation and survival. Certain HER3 mutations have also been identified as oncogenic drivers, making them potential therapeutic targets. In the current study, antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3 directed antibody drug conjugate, was evaluated in tumor models with clinically reported HER3 mutations. MDA-MB-231, a HER3-negative human triple-negative breast cancer cell line, was transduced with lentiviral vectors encoding HER3 wild type (HER3WT), one of 11 HER3 mutations, or HER3 empty vector (HER3EV), in the presence/absence of HER2 overexpression. Targeted delivery of HER3-DXd was assessed using cell-surface binding, lysosomal trafficking, and cell-growth inhibition assays. HER3-DXd bound to the surface of HER3WT and mutant cells in a similar, concentration-dependent manner but not to HER3EV. HER3-DXd was translocated to the lysosome, where time- and concentration-dependent signals were observed in the HER3 mutant and HER3WT cells. HER3-DXd inhibited the growth of HER3WT and HER3 mutant cells. HER3-DXd activity was observed in the presence and absence of HER2 overexpression. These data suggest that HER3-DXd may have activity against tumors expressing wild type HER3 or clinically observed HER3 mutations, supporting further clinical evaluation.