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Jun Lu



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    EP1.03 - Biology (ID 193)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.03-11 - Mechanisms of Gefitinib Plus Pemetrexed on Human Non-Small Cell Lung Cancer (Now Available) (ID 1402)

      08:00 - 18:00  |  Author(s): Jun Lu

      • Abstract
      • Slides

      Background

      Resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) is often acquired in non-small cell lung cancer (NSCLC) patients during treatment. We previously demonstrated that combined treatment with EGFR-TKI gefitinib plus chemotherapy improved progression-free survival (PFS) in NSCLC patients carrying sensitive EGFR mutations.

      Method

      Pharmacological interaction between gefitinib and pemetrexed was evaluated in NSCLC cell line PC-9 using MTT assay. The influence of combined treatment with gefitinib plus pemetrexed on gene expression profiles and signaling pathways has been investigated using microarray and Ingenuity Pathway Analysis (IPA).

      Result

      Synergistic inhibitory effect between gefitinib and pemetrexed was observed in NSCLC cell line PC-9. Figure 1A suggested representative proliferation inhibitory effects of gefitinib, pemetrexed and combined treatment for 48 hours. Figure 1B showed CI values of concurrent gefitinib-pemetrexed treatment in PC-9 NSCLC cell line. CI values at ED50, ED75 and ED90 were shown.

      Furthermore, widespread gene expression changes and critical signaling pathways were induced significantly by combined treatment in PC-9 cells. Figure 2A was heatmap of gene expression prolifes in human NSCLC PC-9 cell line treated with gefitinib (blue), pemetrexed (purple) or gefitinib-pemetrexed combination (orange) with the criteria P<0.05 and ▏fold change ▏>1.5. Genes and samples were listed in rows and columns, respectively. A colour standard for data normalization was shown at the bottom with green representing downregulated genes while red representing upregulated genes. In Figure 2B, pathway enrichment of differential expressed genes was analysed using Ingenuity Pathway Analysis (IPA). Signaling pathways shown here were based on a P<0.0001. Figure 2C showed heatmap of critical pathways affected by combined treatment as compared to gefitinib single treatment. Heatmap colour represented the Z-score of signalling pathways. Z-score>0 meant the signalling pathway was stimulated by related treatment while Z-score<0 meant the signalling pathway was inhibited by related treatment.

      figure 1.jpg

      figure 2.jpg

      Conclusion

      Gene expression profiles revealed potential signaling pathways contributing to the synergism.

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    MA25 - Precision Medicine in Advanced NSCLC (ID 352)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA25.09 - Navigating Anlotinib Precision Therapy Through the Genetic Profiling of Circulating DNA in Non-Small Cell Lung Cancer Patients (Now Available) (ID 1055)

      14:30 - 16:00  |  Presenting Author(s): Jun Lu

      • Abstract
      • Presentation
      • Slides

      Background

      Anlotinib is an oral multi-targeted anti-angiogenic drug, and its clinical predictor for non-small cell lung cancer (NSCLC) patients is still elusive. The aim of this study is to screen predictor for anlotinib via non-invasive genetic profiling of plasma cell free DNA and circulating tumor DNA (cfDNA & ctDNA).

      Method

      Tumor-specific target capture to profile the circulating DNA of ALTER0303 (Evaluating NSCLC clinical anti-tumor efficacy through anlotinib therapy) study participants. Acquired mutations were screened out via comparing genetic profiling between baseline (BL) and progression disease (PD), and were used for anlotinib stratification. Based on the sequencing data at BL, tumor mutation index (TMI) was established from three independent predictors germline and somatic mutation burden (G+S MB), nonsynonymous and synonymous mutation burden (N+S MB) and unfavorable mutation score (UMS), and was used for predicting anlotinib responders. In addition, TMI combined with IDH1Exon4 mutation status also be examined for serving as predictor for anlotinib stratification.

      Result

      Our data firstly indicated no benefit (NB, PFS ≤ 45 days) patients can be mainly excluded via analysis of ARID1A and BRCA2 genetic profiling. Secondly, for the no durable benefit (NDB, 45 days < PFS ≤ 130 days) and durable clinical benefit (DCB, PFS > 130 days) patients, harboring lower mutation burden (G+S MB, N+S MB, and UMS) received more benefit from anlotinib therapy. Subsequently, we found the predictor-TMI can predict anlotinib responders upon discovery cohort (Median PFS: 210 days vs 126 days; p = 0.0238; AUC = 0.77), and validation cohort (Median PFS: 210 days vs 127 days; p = 0.0352) and all patients (Median PFS: 210 days vs 127 days; p = 0.0044) more effectively. Furthermore, the IDH1Exon4 mutation was identified as an unfavorable factor to anlotinib therapy under TMI-based stratification. Lastly, the TMI plus IDH1Exon4 mutation status predict response to anlotinib significantly (Median PFS: 210 days vs 127 days, p < 0.0001, AUC = 0.90; Median OS: 423 days vs 162 days, p < 0.0001, AUC = 0.80).

      Conclusion

      This study provides circulating DNA sequencing-based stratification for underlying anlotinib responders via non-invasive approach, and thus potentially improve clinical outcome for NSCLC patients at 3rd line.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-49 - Roles of CENPU in Lung Adenocarcinoma Progression and Invasion (Now Available) (ID 1382)

      10:15 - 18:15  |  Author(s): Jun Lu

      • Abstract
      • Slides

      Background

      Centromere protein U (CENPU), a centromere protein mediating kinetochore-microtubule interaction, is critical for proper cell cycle and mitosis. It has been implicated that CENPU promotes tumorigenesis in variant malignancies. However, roles of CENPU in lung adenocarcinoma progression and underlying mechanisms remain to be elucidated.

      Method

      CENPU expression in 90 pair lung adenocarcinoma/adjacent normal lung samples was examined with immunohistochemistry (IHC). Then CENPU expression was inhibited with lentiviral-mediated shRNA strategy in human lung adenocarcinoma cell line H1299 to examine the impact of CENPU knockdown for lung adenocarcinoma progression and metastasis. Cell proliferation, colony formation, cell cycle and cell survival were analyzed by Cellomics cell counting method, colonogenesis assay, PI and Annexin V-APC staining respectively while cellular migration and invasion were determined by cell scratch and transwell test. Furthermore, expression of critical factors involved in epithelial-to-mesenchymal transition (EMT) were determined with western blot.

      Result

      CENPU expression was significantly increased in lung adenocarcinomas as compared to adjacent normal lung tissues (fold change=8.54, P<0.0001) (Fig. 1A). Functionl analysis revealed that in human lung adenocarcinoma cell line H1299, CENPU knockdown impaired cell proliferation (Fig. 1B), inhibited colony formation ability (Fig. 1C) and induced cell cycle arrest (Fig. 1D). Additionally, cellular migration and invasion was also inhibited by CENPU knockdown (Fig. 1E-F). It is further shown that E-Cadherin was induced while N-Cadherin and vimentin were inhibited by CENPU knockdown (Fig. 1G), indicating that CENPU was important for EMT process and cancer metastasis.

      fig 1.jpg

      Conclusion

      It showed that CENPU expression is significantly upregulated lung adenocarcinoma tissue. Functional analysis indicated that CENPU is critical for cell proliferation, survival, migration and metastasis in lung adenocarcinoma cell line H1299. CENPU represents a promising target for lung adenocarcinoma therapy.

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    P2.11 - Screening and Early Detection (ID 178)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.11-18 - Circulating Serum KLK5 and L1CAM Levels Potentially Predict Clinical Outcome to Anlotinib Therapy in NSCLC Patients (ID 1074)

      10:15 - 18:15  |  Presenting Author(s): Jun Lu

      • Abstract

      Background

      Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI), which has been demonstrated to be effective upon non-small cell lung cancer (NSCLC) in clinical trials at 3rd line. However, the underlying anlotinib-responsive patients remain elusive. In the present study, we aimed to screen out the potential biomarkers for anlotinib-responsive stratification via transcriptome analysis.

      Method

      Anlotinib-resistant NCI-H1975 cells were established in vitro. Toxicologic effects undergoing anlotinib stress were observed upon NCI-H1975 cells and anlotinib-resistant NCI-H1975 cells, respectively. Transcriptome profiling was performed to screen anlotinib resistance-associated genes between NCI-H1975 cells and anlotinib-resistant NCI-H1975 cells. The correlations between mRNA levels of the anlotinib resistance-associated genes and clinical outcomes of NSCLC patients were analyzed via Kaplan-Meier survival analysis in TCGA cohort. Potential biomarkers for anlotinib-responsive stratification were examined in a 28 patients’ cohort of anlotinib clinical trial (NCT02388919).

      Result

      Anlotinib-induced cytotoxic effects nearly disappeared in anlotinib-resistant NCI-H1975 cells, which are majority attributed to the modulated gene expression of multiple biological processes. Among these biological processes, angiogenesis plays an important role in anlotinib resistance. Up-regulation of angiogenesis-related KLK5 and L1CAM are mostly associated with poor clinical outcome in NSCLC patients. Knockdown of KLK5 and L1CAM contribute to increase anlotinib-induced cytotoxicity upon NCI-H1975 cells and anlotinib-resistant NCI-H1975 cells. High serum levels of KLK5 and L1CAM are also associated with poor anlotinib response in NSCLC patients at 3rd line.

      Conclusion

      This study suggested that serum levels of KLK5 and L1CAM potentially serve as biomarkers for anlotinib-responsive stratification in NSCLC patients at 3rd line.