Science and Technology Production
Congress
Authorship
Ladera M
;
Jencquel, C
;
Bruni S
;
Mercogliano MF
;
SCHILLACI, ROXANA
Date
2025
Publishing House and Editing Place
Medicina
Summary
Information provided by the agent in
SIGEVA
In HER2+ breast cancer, after disease progression, trastuzumab deruxtecan (T-DXd) is the preferred first-line treatment, yet resistance and toxicity remains a challenge. Soluble tumor necrosis factor alpha (sTNF) induces trastuzumab resistance via mucin 4 (MUC4) upregulation, and its neutralization with the dominant-negative protein INB03 (DN) restores sensitivity. We evaluated whether sTNF blockade enhances T-DXd efficacy and modulates immune response in HER2+ preclinical models. Female nude m...
In HER2+ breast cancer, after disease progression, trastuzumab deruxtecan (T-DXd) is the preferred first-line treatment, yet resistance and toxicity remains a challenge. Soluble tumor necrosis factor alpha (sTNF) induces trastuzumab resistance via mucin 4 (MUC4) upregulation, and its neutralization with the dominant-negative protein INB03 (DN) restores sensitivity. We evaluated whether sTNF blockade enhances T-DXd efficacy and modulates immune response in HER2+ preclinical models. Female nude mice bearing JIMT-1 tumors received IgG, T-DXd (5, 2.5, or 1.25 mg/kg), DN (10 mg/kg), or the combinations, while FVB mice with syngeneic Fo5 tumors received IgG, T-DXd (1.25 mg/kg), DN, or both. In JIMT-1 tumors, T-DXd inhibited growth by 83% (p<0.0001), 61% (p<0.001), and 37% (p<0.05), respectively, whereas combination with DN increased inhibition to 98% (p<0.0001), 81% (p<0.0001), and 73% (p<0.0001),. Similar results were observed in Fo5 tumors with the dose of 1.25mg/kg T-DXd. DN addition to T-DXd enhanced significantly macrophage tumor infiltration and M1-like polarization in both models. In Fo5 tumors, DN further increased CD8⁺ T cell infiltration. Because DXd was hypothesized to activate type I interferon (IFN-I) signaling, we examined cGAS and ISG15 expression. In JIMT-1, T-DXd increased cGAS and ISG15 expression, with DN potentiating these effects, particularly at lower T-DXd doses. In Fo5, DN and T-DXd independently increased cGAS/ISG15, with additive effect when combined. Thus, sTNF blockade augments T-DXd antitumor activity, enabling lower effective doses, reshaping the immune microenvironment, and engaging IFN-I pathways. These findings support DN as a potential adjuvant to improve T-DXd efficacy in HER2+ breast cancer.
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Key Words
BREAST CANCERT-DXdTNF