Der PI3K- Signalweg als therapeutische Zielstruktur von Leiomyosarkomen - Präklinische Validierung mithilfe humaner Xenograftmodelle

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Targeting the PI3K- and MAPK pathway in leiomyosarcoma Leiomyosarcomas (LMS) are one of the most common soft tissue tumors in humans and typically show smooth-muscle differentiation. While these tumors can arise anywhere in the body, most LMS are found in the retroperitoneum, the extremities and the uterus. LMS are characterized by their aggressive growth and in many patients, at first diagnosis, metastases have already spread to other sites like lung, liver or bones. Despite intense, multimodal therapies the majority of patients die because of metastatic events. As of yet, no targeted therapies, exploiting concrete genetic aberrations have been approved for LMS treatment. Various studies have shown a dysregulation and oncogenic addiction of the PI3K signaling pathway in LMS tumors, which could be exploited to establish new therapy concepts for patients. In the current study we evaluated the inhibition of the PI3K signaling pathway in LMS cell lines in vitro and in vivo. We show that dual PI3K/mTOR inhibitors are superior to inhibitors of PI3K or mTOR alone. In addition we identified a compensatory feedback mechanism by which induction of MAPK signaling counteracts PI3K/mTOR inhibition. This effect could be successfully abrogated using the MEK inhibitor trametinib. Dose-combination experiments with the PI3K/mTOR inhibitor gedatolisib and trametinib revealed synergistic effects in one LMS cell line. In vivo experiments with a nude mouse LMS xenograft model confirmed the superior efficacy of combined treatment with these inhibitors, as observed by a significantly reduced tumor volume in combined treatment vs. control group. These promising preclinical results could serve as a basis for new therapeutical concepts for LMS patients.

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Steven Knospe

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Biochemie Kinasen Transfektion Xenotransplantate Zellkultur cell culture kinases leiomyosarcoma polymerase chain reaction transfection xenografts

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