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Combination treatment with intravesical interferon-alpha gene therapy and an oral pan-ErbB receptor family blocker improves survival in mice with bladder cancer
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DOI：10.3389/fmolb.2026.1804161.png)
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Abstract
En 中文
IntroductionIntravesical interferon-alpha (IFNα) gene therapy is approved by the FDA for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Identifying resistance mechanisms and deploying targeted combination treatment strategies is a rational approach to improving treatment responses. We identified the ErbB pathway as a resistance mechanism to IFNα gene therapy; and we hypothesized that combination treatment with an ErbB pathway blocker and IFN-α could improve outcomes in resistant tumors.MethodsMurine bladder cancer cells were treated in vitro with lentiviral IFNα (LV-IFNα) gene therapy; with/without afatinib (Afa); a pan-ErbB inhibitor; and cell viability and migration assays were performed. In vivo studies were conducted in a syngeneic MB49 orthotopic murine bladder cancer model; and mice were randomized into five treatment groups and treated with single treatments: Ctrl (vehicle); LV-Ctrl; LV-IFNα; and combination treatments with LV-Ctrl/Afa or LV-IFNα/Afa.ResultsCombination therapy with LV-IFNα/Afa significantly reduced MB49 cell viability in vitro compared to all other treatment conditions. This additive effect on cell viability appeared to be driven by a combination of early-cytostatic and late-cytolytic effects. The combination treatment also markedly inhibited cell migration. Finally; the in vivo studies demonstrated improved overall survival (OS) with LV-IFNα/Afa (median OS was 49 days in the LV-IFNα/Afa group vs. 15; 14; 29; and 26 days in Ctrl; LV-Ctrl; LV-IFNα; and LV-Ctrl/Afa groups; respectively; log-rank p < 0.001).ConclusionOur findings suggest that the ErbB pathway may serve as a clinically actionable resistance mechanism to intravesical IFNα gene therapy and; when targeted concurrently; it may improve treatment efficacy.
Keywords:
bladder cancer
gene therapy
epidermal growth factor receptor
mice
afatinib
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