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Toshio Fujino

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-41 - In Vitro Evaluation for Optimal MET-TKI Selection in Lung Cancers with MET Mutations Including Exon 14 Skipping (ID 12825)

      16:45 - 18:00  |  Presenting Author(s): Toshio Fujino

      • Abstract


      MET exon 14 skipping mutation present in 3-5% of adenocarcinoma of the lung is an emerging driver gene alteration. Clinical responses of these tumors to MET-TKI have been reported. However, response rates are not very satisfactory compared with EGFR/ALK/ROS1 TKI. Therefore, it is necessary to create in vitro model system to understand sensitivity/resistance mechanism for various types of MET-TKI, to establish optimal treatment strategy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We introduced MET exon 14 skipping mutation as well as Y1003F, D1010Y which had been also reported to be present in lung cancer, to mouse pro-B cell line, Ba/F3. Since Ba/F3 requires interleukin 3 (IL-3) for its growth, IL-3 independent growth of Ba/F3 indicates that transduced mutation is oncogenic. The growth inhibitory assays were then performed using 9 MET-TKIs that include all classes of MET-TKIs ; Type Ia (crizotinib), Type Ib (capmatinib, tepotinib, savolitinib and AMG337) , Type II (cabozantinib, merestinib and glesatinib) and Type III (tivantinib).

      4c3880bb027f159e801041b1021e88e8 Result

      Ba/F3 transfected with wild-type MET did not grow in the absence of IL-3, while all transfected with any of three mutated MET did so. In general, all type Ia/b / type II inhibitors were active for any of 3 MET mutations. Interestingly MET point mutations (Y1003F/D1010Y) were more sensitive to type Ib inhibitors except AMG337 than type II, while exon 14 skipping was likely to be more sensitive to type II inhibitors than type Ib compared with point mutations. IC50 / Cmax of cabozontinib was least for exon 14 skipping while that of capmatinib was least for Y1003F and D1010Y, suggesting most promising activity of these drugs (Table).


      8eea62084ca7e541d918e823422bd82e Conclusion

      We found that the MET exon 14 skipping, Y1003F, and D1010Y mutations were all oncogenic in Ba/F3 system. Several type I/II inhibitors especially cabozantinib and capmatinib are expected to be active for treating lung cancer patients with MET mutations.