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A. Estrada-Bernal

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    MINI 14 - Pre-Clinical Therapy (ID 119)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI14.04 - In Vitro and in Vivo Evaluation of the Kinase Inhibitor, MGCD516, in TRK and RET Fusion Cancer Cells (ID 2756)

      10:45 - 12:15  |  Author(s): A. Estrada-Bernal

      • Abstract
      • Presentation
      • Slides

      The paradigm of treating oncogene-selected patients with non-small cell lung cancer (NSCLC) and other malignancies using targeted kinase inhibitors has significant improved patient outcomes, specifically for patients harboring ALK, ROS1, and EGFR oncogenes. Additional oncogene targets that may benefit from this therapeutic strategy are therefore of immense interest. NTRK1 (TRKA) and RET gene fusions are recently identified oncogenes in NSCLC (and other malignancies) without approved kinase inhibitors. MGCD516 is a spectrum-selective tyrosine kinase inhibitor with activity against TRKA, RET, MET, VEGFR, PDGFR, AXL, and Eph family of receptors. In this report, we evaluated MGCD516 in vitro activity in cell lines with an NTRK1, NTRK3, or RET gene rearrangements. Additionally, we used a mouse xenograft model to assess the in vivo effects of MGCD516 on tumors harboring TRKA and RET fusions.

      Gene fusion positive cell lines, KM12 (TPM3-NTRK1), CUTO-3 (MPRIP-NTRK1), MO-91 (ETV6-NTRK3) and LC-2/Ad (CCDC6-RET) were used for the in vitro evaluation of MGCD516 inhibitory activity against these oncogenic fusion kinases. Cell lines were assessed for cell viability (MTS-base proliferation assay) and downstream signaling pathways (immunoblot analysis) upon treatment with MGCD516. For in vivo studies, xenograft models of TRKA fusion tumors (CUTO-3 and KM12) and RET fusion tumors (LC-2/Ad and a tumor biopsy from a KIF5B-RET patient) were generated in athymic nude mice. Once tumors reached ~200cm[3], a single daily dose of 5mg/kg, 10mg/kg or 20mg/kg of MGCD516 was given to mice by oral gavage. Mice in the control arm of the study were gavaged with vehicle at similar volume. Tumor size and weight measurement of mice were assessed 3 times per week.

      MGCD516 had notable in vitro effects on the proliferation of cell lines with either RET fusion (LC-2/Ad), TRKA fusion (KM12 and CUTO-3) or TRKC fusion (MO-91) with low nanomolar IC~50~. Western blot analyses showed specific loss of phosphorylated CCDC6-RET or TRKA/C fusion protein and decreased activation of the AKT and MAPK signaling pathways when cells were treated with MGCD516. In mouse xenograft studies, tumors with TRKA fusion displayed dose-dependent growth inhibition at 5mg/kg and 10mg/kg daily doses of MGCD516 compared to controls. Notably, we observed tumor regression in the mice originally assigned to the vehicle control arm once we enrolled the mice on a 10mg/kg or 20mg/kg daily regimen of MGCD516. Comparable to the TRKA fusion xenografts studies, RET fusion tumors were growth inhibited with a 20mg/kg daily dose of MGCD516.

      The spectrum-selective tyrosine kinase inhibitor, MGCD516, demonstrates potent in vitro activity in multiple TRKA/C and RET fusion cancer cell line models and in vivo activity against TRKA and RET fusion kinase in murine xenograft models. A phase I clinical trial of MGCD516 is ongoing and the inclusion of patients with TRK and RET fusion is planned.

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