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Yi-Chen Yeh



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    EP1.14 - Targeted Therapy (ID 204)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.14-35 - Squamous Cell Carcinoma Transformation After Acquired Resistance to OsimertinibĀ  (Now Available) (ID 85)

      08:00 - 18:00  |  Author(s): Yi-Chen Yeh

      • Abstract
      • Slides

      Background

      Osimertinib is a third-generation epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) for the management of NSCLC carrying EGFR T790M mutation after acquired resistance to prior EGFR-TKI and is now the preferred therapy in the front-line. The resistance mechanism of osimertinib, including histologic transformation had been reported, mostly small cell carcinoma.

      Method

      Here we a patient with lung adenocarcinoma with uncommon EGFR H835L +L833V + T790M mutation who developed progressive lung atelectasis after acquired resistance to osimertinib. Bronchoscopic biopsy over the endobronchial tumor was done and the pathology report showed squamous cell carcinoma.

      Result

      Mutation analysis of the squamous cell carcinoma performed by next generation sequencing (FoundationOneĀ® CDx) was performed and reveled complex genomic alteration including EGFR H835L, L833V and T790M mutation, TP53 mutation and mTOR amplification. Squamous cell transformation after acquired resistance to osimeritinib was diagnosed. Then the patient was treated with a mTOR inhibitor, everolimus (5mg /day) plus osimertinib. One month after treatment an initial tumor response was observed, however, a progression occurred after 3 months of treatment.

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      Conclusion

      Squamous cell transformation is a rare manifestation of osimertinib resistance, further research is need to investigate the underlying mechanism of this histologic change and discover the proper treatment strategy.

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    MA15 - Usage of Computer and Molecular Analysis in Treatment Selection and Disease Prognostication (ID 141)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      MA15.01 - Cellular Prion Protein Transcriptionally Regulated by NFIL3 Enhances Lung Cancer Cell Lamellipodium Formation and Migration (Now Available) (ID 151)

      15:45 - 17:15  |  Author(s): Yi-Chen Yeh

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor invasion and metastasis are the major causes of treatment failure and mortality in lung cancer patients. However, the precise molecular targets responsible for tumor invasion remain unclear.

      Method

      In this study, we identified a group of genes with differential expression in in situ and invasive lung adenocarcinoma tissues by cDNA microarray analysis; among these genes we further characterized the association of the upregulation of PRNP, the gene encoding cellular Prion protein (PrPc), with lung adenocarcinoma invasiveness through immunohistochemistry and in situ hybridization analysis on clinical tissues. The roles of PrPc in lung cancer cell lines were also verified by using immunofluorescence staining, in vitro transwell assay and in vivo metastasis mouse model. In addition, the impact of PrPc on the activation of the JNK signaling pathway was investigated by Western blot analysis. Finally, luciferase reporter assay and chromatin immunoprecipitation assay were used to identify the transcriptional activators of PRNP.

      Result

      Immunohistochemistry on clinical specimens showed association of PrPc expression with invasive but not in situ lung adenocarcinoma. Consistently, the expression of PrPc was higher in the highly invasive than in the lowly invasive lung adenocarcinoma cell lines. Knockdown of PrPc expression in cultured lung adenocarcinoma cells decreased their lamellipodium formation, in vitro migration and invasion, and in vivo experimental lung metastasis. Phosphorylation of JNKs was found to correlate with PrPc expression and the inhibition of JNKs suppressed the PrPc-induced up-regulation of lamellipodium formation, cell migration, and invasion. Moreover, we identified the nuclear factor, interleukin 3 regulated (NFIL3) protein as a transcriptional activator of the PRNP promoter. Accordingly, NFIL3 promoted lung cancer cell migration and invasion in a PrPc-dependent manner. High NFIL3 expression in clinical specimens of lung adenocarcinoma was also associated with tumor invasiveness and poor survival of patients.

      Conclusion

      Our observations suggest that PRNP expression is associated with the invasiveness of lung adenocarcinoma, and cell line model demonstrated that PrPc serves as a critical factor for lung cancer cell lamellipodia formation, migration and invasion via JNK signaling. A novel transcription factor, NFIL3, was identified to upregulate PRNP expression in lung cancer cells; further characterizations showed that NFIL3 promotes lung cancer cell migration through PrPc-dependent manner. Moreover, high NFIL3 expression was found to be associated with lung cancer invasiveness in clinical tissues. Overall, NFIL3/PrPc axis plays a critical role in lung cancer invasiveness and metastasis, and may be the potential therapeutic targets in the future.

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