Dual‐targeting therapy against <scp>HER3</scp>/<scp>MET</scp> in human colorectal cancers

Yamasaki, Akitaka; Miyake, Rikuto; Hara, Yuta; Okuno, H.; Imaida, Takuya; Okita, Kouki; Okazaki, Shogo; Akiyama, Yasutoshi; Hirotani, Kenji; Endo, Yuichi; Masuko, Kazue; Masuko, Takashi; Tomioka, Y.

doi:10.1002/cam4.5673

Cited by 3 publications

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“…The overexpression of growth factor receptors such as EGFR, HER3, MET, and IGF1R, may be a major mechanism for the resistance of cancer cells to αHER therapies (Vu & Claret, 2012), and, thus, their combination with BsAb therapies to overcome cancer resistance is being examined (Juric et al, 2015). We showed that high affinity rather than total binding of αHER3 mAb improved combination therapies with αHER1 or αHER2 drugs (Okita et al, 2021), and suggested the efficacy of the dual targeting of HER3 and MET in the treatment of colorectal cancers (Yamasaki et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

CD98 regulates the phosphorylation of HER2 and a bispecific anti‐HER2/CD98 antibody inhibits the growth signal of human breast cancer cells

et al. 2023

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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.

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Section: Introductionmentioning

confidence: 99%

CD98 regulates the phosphorylation of HER2 and a bispecific anti‐HER2/CD98 antibody inhibits the growth signal of human breast cancer cells

et al. 2023

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Dual‐targeting therapy against HER3/MET in human colorectal cancers

et al. 2023

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Background Colorectal cancer (CRC) is the most common malignancy in the world, and novel molecular targeted therapies for CRC have been vigorously pursued. We searched for novel combination therapies based on the expression patterns of membrane proteins in CRC cell lines. Results A positive correlation was observed between the expression of human pidermal growth factor receptor (HER) 3 and mesenchymal‐to‐epithelial transition factor (MET) on the cell surface of CRC cell lines. The brief stimulation of HER3/MET‐high SW1116 CRC cells with both neuregulin‐1 (NRG1) and hepatocyte growth factor enhanced ERK phosphorylation and cell proliferation more than each stimulation alone. In addition, a prolonged NRG1 stimulation resulted in the tyrosine phosphorylation of MET. In this context, the Forkhead Box protein M1 (FOXM1)‐regulated tyrosine phosphorylation of MET by NRG1 was demonstrated, suggesting the existence of a signaling pathway mediated by FOXM1 upon the NRG1 stimulation. Since the co‐expression of HER3 and MET was also demonstrated in in vivo CRC tissues by immunohistochemistry, we investigated whether the co‐inhibition of HER3 and MET could be an effective therapy for CRC. We established HER3‐and/or MET‐KO SW1116 cell lines, and HER3/MET‐double KO resulted in the inhibition of in vitro cell proliferation and in vivo tumor growth in nude mice by SW1116 cells. Furthermore, the combination of patritumab, an anti‐HER3 fully human mAb, and PHA665752, a MET inhibitor, markedly inhibited in vitro cell proliferation, 3D‐colony formation, and in vivo tumor growth in nude mice by SW1116 cells Conclusion The dual targeting of HER3/MET has potential as CRC therapy.

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The Evolving Paradigm of Antibody–Drug Conjugates Targeting the ErbB/HER Family of Receptor Tyrosine Kinases

High,

Guernsey,

Subramanian

et al. 2024

Pharmaceutics

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Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance and systemic toxicities. Antibody–drug conjugates (ADCs) are one of the most rapidly expanding classes of anti-cancer therapeutics with 13 presently approved by the FDA. Importantly, ADCs represent a promising therapeutic option with the potential to overcome traditional HER-targeted therapy resistance by delivering highly potent cytotoxins specifically to HER-overexpressing cancer cells and exerting both mAb- and payload-mediated antitumor efficacy. The clinical utility of HER-targeted ADCs is exemplified by the immense success of HER2-targeted ADCs including trastuzumab emtansine and trastuzumab deruxtecan. Still, strategies to improve upon existing HER2-targeted ADCs as well as the development of ADCs against other HER family members, particularly EGFR and HER3, are of great interest. To date, no HER4-targeting ADCs have been reported. In this review, we extensively detail clinical-stage EGFR-, HER2-, and HER3-targeting monospecific ADCs as well as novel clinical and pre-clinical bispecific ADCs (bsADCs) directed against this receptor family. We close by discussing nascent trends in the development of HER-targeting ADCs, including novel ADC payloads and HER ligand-targeted ADCs.

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Dual‐targeting therapy against HER3/MET in human colorectal cancers

Cited by 3 publications

References 54 publications

CD98 regulates the phosphorylation of HER2 and a bispecific anti‐HER2/CD98 antibody inhibits the growth signal of human breast cancer cells

CD98 regulates the phosphorylation of HER2 and a bispecific anti‐HER2/CD98 antibody inhibits the growth signal of human breast cancer cells

Dual‐targeting therapy against HER3/MET in human colorectal cancers

The Evolving Paradigm of Antibody–Drug Conjugates Targeting the ErbB/HER Family of Receptor Tyrosine Kinases

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