The HER2 S310F Mutant Can Form an Active Heterodimer with the EGFR, Which Can Be Inhibited by Cetuximab but Not by Trastuzumab as well as Pertuzumab
| Autor: | Seongyeong Kim, Jung Won Shin, Seock-Ah Im, Soohyun Kim, Byungsan Choi, Suji Ha, Tae-Young Yoon, Junho Chung |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell Survival Receptor ErbB-2 EGFR Mutant lcsh:QR1-502 Heterodimerization Cetuximab TIR microscope Antibodies Monoclonal Humanized Biochemistry lcsh:Microbiology Article 03 medical and health sciences Antineoplastic Agents Immunological 0302 clinical medicine Gefitinib Trastuzumab HER2 Tumor Cells Cultured medicine Humans skin and connective tissue diseases Receptor neoplasms Molecular Biology Pertuzumab Cell growth Chemistry Recombinant Proteins ErbB Receptors 030104 developmental biology 030220 oncology & carcinogenesis Mutation Cancer research Phosphorylation medicine.drug |
| Zdroj: | Biomolecules Biomolecules, Vol 9, Iss 10, p 629 (2019) Volume 9 Issue 10 |
| ISSN: | 2218-273X |
| DOI: | 10.3390/biom9100629 |
| Popis: | G309 or S310 mutations on the HER2 extracellular domain II induce receptor activation. Clinically, S310F is most frequent among HER2 extracellular domain mutations and patients with the S310F mutation without HER2 amplification responded to trastuzumab with or without the pertuzumab combination. However, the ability of S310F mutant to form homodimers or heterodimers with wild-type HER2 and other HER receptors, or their reactivity to trastuzumab and pertuzumab treatments, has not been reported. We overexpressed S310F as well as G309A, G309E and S310Y HER2 mutants and tested their reactivity to trastuzumab and pertuzumab. All mutants reacted to trastuzumab, but S310F mutant did not react to pertuzumab along with S310Y or G309E mutants. Thereafter, we tested the effects of trastuzumab and pertuzumab on 5637 cell line expressing both wild-type HER2 and S310F mutant. The ligand-independent HER2 homodimerization blocking antibody, trastuzumab, did not inhibit the activation of the HER2 receptor, suggesting that the S310F HER2 mutant did not form homodimers or heterodimers with wild-type HER2. Because 5637 cells overexpressed the EGFR, the effects of cetuximab and gefitinib were determined, and both inhibited the activation of HER2 and significantly reduced cell growth. Because pertuzumab did not inhibit the phosphorylation of HER2 while it bound to wild-type HER2, EGFR-mediated phosphorylation is expected to occur on the S310F mutant. To confirm whether the S310F mutant HER2 retained its affinity to the EGFR, single molecule interaction analyses using TIRF microscopy were performed, which showed that S310F mutant successfully formed complexes with EGFR. In conclusion, HER2 S310F mutant can form an active heterodimer with the EGFR and it can be inhibited by cetuximab, but not by trastuzumab in combination with pertuzumab. |
| Databáze: | OpenAIRE |
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