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| Title | Selective targeting of oncogenic hotspot mutations of the HER2 extracellular domain. |
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| Journal, issue, pages | Nat Chem Biol, Vol. 21, Issue 5, Page 706-715, Year 2025 |
| Publish date | Oct 22, 2024 |
 Authors | Injin Bang / Takamitsu Hattori / Nadia Leloup / Alexis Corrado / Atekana Nyamaa / Akiko Koide / Ken Geles / Elizabeth Buck / Shohei Koide /  |
| PubMed Abstract | Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been ...Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been identified in receptor tyrosine kinases including HER2. However, it is challenging to selectively target a point mutant, while sparing the wild-type protein. Here we developed antibodies selective to HER2 S310F and S310Y, the two most common oncogenic mutations in the HER2 ECD, via combinatorial library screening and structure-guided design. Cryogenic-electron microscopy structures of the HER2 S310F homodimer and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimics the dimerization arm of HER2 and thus inhibit HER2 dimerization. These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development. |
 External links | Nat Chem Biol / PubMed:39438724 |
| Methods | EM (single particle) |
| Resolution | 2.61 - 2.67 Å |
| Structure data | EMDB-43439, PDB-8vqd: EMDB-43440, PDB-8vqe: |
| Source |
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 Keywords | SIGNALING PROTEIN / HER2 / Fab / Tyrosine kinase receptor / Receptor tyrosine kinase / oncogenic mutation |
homo sapiens (human)