Zusammenfassung
Trastuzumab ist eine hocheffektive Waffe in der Behandlung des HER2-positiven Mammakarzinoms. Dieser monoklonale Antikörper ist sowohl in der metastasierten als auch adjuvanten Situation zur Behandlung zugelassen. Trotzdem bleiben viele Fragen über den optimalen Einsatz weitgehend offen. Insbesondere die Tatsache, dass ein signifikanter Anteil HER-2 positiver Mammakarzinome primär nicht auf eine Trastuzumab-Therapie ansprechen oder nach etwa einem Jahr eine Resistenz gegenüber diesem Antikörper entwickeln, bedarf intensiver Forschungsarbeit. In dieser Zusammenfassung des aktuellen Wissenstands über die Resistenzmechanismen gegenüber Trastuzumab werden als mögliche Ursachen der extrazelluläre trunkierte HER2-Rezeptor, der Verlust des Tumor-Suppressors PTEN, die Aktivierung alternativer Signalwege (z. B. IGFR etc.) und der Verlust der Rezeptor-Antikörper-Interaktion diskutiert. Die Entwicklung von Strategien zur Aufhebung der Resistenzentwicklung stellt ein wichtiges Betätigungsfeld bei der Behandlung des HER2-neu positiven Mammakarzinoms dar.
Summary
Trastuzumab has shown significant efficacy in HER2-overexpressing breast cancers and is approved for patients whose tumors carry this abnormality, both in the metastatic and in the adjuvant settings. However, several issues about its optimal use remain unresolved. Many breast cancer patients with HER2 overexpression do not respond to initial therapy with trastuzumab (Herceptin®), and a vast majority of these develop resistance to this monoclonal antibody within one year. This review discusses the molecular mechanisms leading to the development of trastuzumab resistance, including circulating HER2 extracellular domain, loss of PTEN, activation of alternative pathways (e.g. IGFR), and receptor-antibody interaction block. Additionally, the possibility of exploring these aberrations as therapeutic targets that potentially overcome resistance to trastuzumab is highlighted.
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Hubalek, M., Brunner, C., Matthä, K. et al. Resistance to HER2-targeted therapy: mechanisms of trastuzumab resistance and possible strategies to overcome unresponsiveness to treatment. Wien Med Wochenschr 160, 506–512 (2010). https://doi.org/10.1007/s10354-010-0838-6
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DOI: https://doi.org/10.1007/s10354-010-0838-6