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Seiji Yano



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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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      P1.13-38 - Inter-Organ Heterogeneity on Mechanisms of Targeted Drug Resistance -Central Nervous System (CNS) vs Extra CNS- (ID 13047)

      16:45 - 18:00  |  Presenting Author(s): Seiji Yano

      • Abstract
      • Slides

      Background

      Molecular-targeted drugs are generally effective against tumors containing driver oncogenes, such as EGFR, ALK, and NTRK1. However, patients harboring these oncogenes frequently experience a progression of central nervous system (CNS) metastasis, such as brain metastasis and leptomeningeal carcinomatosis (LMC), during treatment. While secondary mutations including EGFR-T790M, ALK-L1196M, and NTRK1-G595R, are known to induce highly resistance to corresponding targeted drugs, involvement of these highly resistance mutations in CNS metastasis resistance is largely unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We developed various in vivo imaging models for brain metastasis and LMC with human cancer cell lines, including the EGFR-exon 19 deletion-positive PC-9 lung adenocarcinoma cells, the EML4-ALK-positive A925L lung adenocarcinoma cells, and TPM3-NTRK1-positive KM12SM colon cancer cells. Using these CNS metastasis models, we examined the inter-organ heterogeneity on mechanisms of resistance to targeted drugs.

      4c3880bb027f159e801041b1021e88e8 Result

      While PC-9 cells inoculated in subcutaneous space acquired EGFR tyrosine kinase inhibitor (EGFR-TKI) resistance by EGFR-T790M mutation, they inoculated in leptomeningeal space became resistance by MET copy number gain. Unlike EGFR-T790M mutation, MET copy number gain could cause intermediate resistance to EGFR-TKI in vitro. Similarly, A925L cells inoculated in leptomeningeal space acquired ALK-TKI resistance by EGFR ligand overexpression. Moreover, KM12SM cells inoculated in the brain acquired entrectinib resistance by NTRK1-G667C mutation. Since both EGFR ligand overexpression and NTRK1-G667C mutation caused intermediate resistance to targeted drugs in vitro, mechanisms which cause intermediate resistance may be sufficient to develop resistant tumors in CNS presumably due to limited drug distribution to CNS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These observations indicate inter-organ heterogeneity on mechanisms of targeted drug resistance. Therefore, careful diagnosis of resistance mechanism in CNS metastasis may be necessary when treat the patients who develop CNS metastasis with targeted drug resistance.

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