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CD98 regulates the phosphorylation of HER2 and a bispecific anti-HER2/CD98 antibody inhibits the growth signal of human breast cancer cells |
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| Authors: | Akitaka Yamasaki Kumiko Maruyama-Takahashi Kento Nishida Shogo Okazaki Kouki Okita Yasutoshi Akiyama Hideaki Suzuki Yuichi Endo Kazue Masuko Takashi Masuko Yoshihisa Tomioka |
| Affiliation: | 1. Laboratory of Oncology Pharmacy Practice and Science, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai-shi, Japan Cell Biology Laboratory, Faculty of Pharmacy, Kindai University, Higashiosaka-shi, Japan;2. Department of Hygienic Chemistry (April 1975–March 1994), Pharmaceutical Institute, Tohoku University, Sendai-shi, Japan;3. Laboratory of Oncology Pharmacy Practice and Science, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai-shi, Japan;4. Cell Biology Laboratory, Faculty of Pharmacy, Kindai University, Higashiosaka-shi, Japan Department of Microbiology, Division of Immunology and Pathobiology, Nihon University School of Density, Chiyoda-ku, Japan;5. Cell Biology Laboratory, Faculty of Pharmacy, Kindai University, Higashiosaka-shi, Japan Production and Manufacturing, Carna Biosciences Inc., Chuo-ku, Japan;6. Laboratory of Natural Drug Resources, Faculty of Pharmacy, Kindai University, Higashiosaka-shi, Japan;7. Cell Biology Laboratory, Faculty of Pharmacy, Kindai University, Higashiosaka-shi, Japan Department of Hygienic Chemistry (April 1975–March 1994), Pharmaceutical Institute, Tohoku University, Sendai-shi, Japan;8. Cell Biology Laboratory, Faculty of Pharmacy, Kindai University, Higashiosaka-shi, Japan;9. Laboratory of Oncology Pharmacy Practice and Science, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai-shi, Japan Department of Hygienic Chemistry (April 1975–March 1994), Pharmaceutical Institute, Tohoku University, Sendai-shi, Japan |
| Abstract: | Human epidermal growth factor receptor (HER) family proteins are currently major targets of therapeutic monoclonal antibodies against various epithelial cancers. However, the resistance of cancer cells to HER family-targeted therapies, which may be caused by cancer heterogeneity and persistent HER phosphorylation, often reduces overall therapeutic effects. We herein showed that a newly discovered molecular complex between CD98 and HER2 affected HER function and cancer cell growth. The immunoprecipitation of the HER2 or HER3 protein from lysates of SKBR3 breast cancer (BrCa) cells revealed the HER2-CD98 or HER3-CD98 complex. The knockdown of CD98 by small interfering RNAs inhibited the phosphorylation of HER2 in SKBR3 cells. A bispecific antibody (BsAb) that recognized the HER2 and CD98 proteins was constructed from a humanized anti-HER2 (SER4) IgG and an anti-CD98 (HBJ127) single chain variable fragment, and this BsAb significantly inhibited the cell growth of SKBR3 cells. Prior to the inhibition of AKT phosphorylation, BsAb inhibited the phosphorylation of HER2, however, significant inhibition of HER2 phosphorylation was not observed in anti-HER2 pertuzumab, trastuzumab, SER4 or anti-CD98 HBJ127 in SKBR3 cells. The dual targeting of HER2 and CD98 has potential as a new therapeutic strategy for BrCa. |
| Keywords: | bispecific antibody breast cancer CD98 human epidermal growth receptor family knockdown |