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- W4362542093 abstract "<div>Abstract<p>Triple-negative breast cancer (TNBC) is a highly diverse group of malignant neoplasia with poor outcome. Currently, the lack of effective therapy has fostered a major effort to discover new targets to treat this malignant cancer. Here we identified the RON receptor tyrosine kinase as a therapeutic target for potential TNBC treatment. We analyzed RON expression in 168 primary TNBC samples via tissue microarray using anti-RON IHC staining and demonstrated that RON was widely expressed in 76.8% TNBC samples with overexpression in 76 cases (45.2%). These results provide the molecular basis to target RON for TNBC therapy. To this end, anti-RON monoclonal antibody Zt/g4-drug monomethyl auristatin E conjugate (Zt/g4-MMAE) was developed with a drug to antibody ratio of 3.29 and tested in a panel of TNBC cell lines with different phenotypes. <i>In vitro</i>, Zt/g4-MMAE rapidly induced RON internalization, resulted in cell-cycle arrest followed by massive cell death. The calculated IC<sub>50</sub> values ranged from 0.06 to 3.46 μg/mL dependent on individual TNBC cell lines tested. Zt/g4-MMAE also effectively killed TNBC stem-like cells with RON<sup>+</sup>/CD44<sup>+</sup>/CD24<sup>−</sup> phenotypes and RON-negative TNBC cells through the bystander effect. <i>In vivo</i>, Zt/g4-MMAE at 10 mg/kg in a Q12 × 2 regimen completely eradicated TNBC xenografts without the regrowth of xenograft tumors. In conclusion, increased RON expression is a pathogenic feature in primary TNBC samples. Zt/g4-MMAE is highly effective in eradicating TNBC xenografts in preclinical models. These findings lay the foundation for using anti-RON Zt/g4-MMAE in clinical trials as a novel strategy for TNBC treatment.</p></div>" @default.
- W4362542093 created "2023-04-06" @default.
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- W4362542093 date "2023-04-03" @default.
- W4362542093 modified "2023-09-25" @default.
- W4362542093 title "Data from RON Receptor Tyrosine Kinase as a Therapeutic Target for Eradication of Triple-Negative Breast Cancer: Efficacy of Anti-RON ADC Zt/g4-MMAE" @default.
- W4362542093 doi "https://doi.org/10.1158/1535-7163.c.6538086.v1" @default.
- W4362542093 hasPublicationYear "2023" @default.
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