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C. Zhao



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    MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 11.07 - Exosomes-Transmitted MicroRNAs Promote EGFR-TKIs Resistance in NSCLC by Activating PI3K/AKT Signaling Pathway (ID 9446)

      11:00 - 12:30  |  Author(s): C. Zhao

      • Abstract
      • Presentation
      • Slides

      Background:
      Acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) resistance is a major factor contributing to targeted therapy failure in EGFR mutant non-small cell lung cancer (NSCLC), among which T790M mutation accounts for 50-60%. Emerging evidence has shown that as mediators between cells, exosomes shed by drug resistant cancer cells have the ability to horizontally transfer drug resistant phenotype to drug sensitive cells, which has been described as an important mechanism of dissemination of drug resistance. However, whether exosomes derived from EGFR-TKIs resistant NSCLC cells harboring T790M mutation could transfer resistance to sensitive cells has not been understood and the potential mechanism also remains unknown.

      Method:
      Exosomes were isolated from supernatants of T790M mutant NSCLC cell line (H1975) and characterized by transmission electron microscopy, nanosight and western blot. Their potential roles in mediating gefitinib resistance in sensitive cell line (PC9) were investigated in vitro and in vivo. Cell viability and the effects of exosomes on downstream signaling pathways were analyzed by CCK-8 assays and western blot. The roles of exosomes in regulating gefitinib resistance in vivo were assessed by subcutaneous transplantation tumor model in athymic nude mice. Exosomes miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were used for exploring the underlying mechanism.

      Result:
      Exosomes isolated from conditioned medium of NSCLC cell lines were cup-shaped membranous vesicles with a diameter of 30-100 nm and expressed the exosomal marker CD63. Exosomes derived from H1975 could transmit gefitinib resistance to PC9 (P<0.01) in vitro while exosomes released from PC9 cell don’t have this effect. Treatment of PC9 with H1975-derived exosomes and the inhibitor of exosomes production (GW4869) could restore gefitinib response. In vivo, the tumor volume of xenograft model of PC9 cells treated with gefitinib plus H1975-derived exosomes was significantly larger than those mice treated with gefitinib alone (P<0.05). Furthermore, H1975 xenografts could disseminate gefitinib resistance to PC9 xenografts in the same mice. This difference disappeared by the addition of GW4869. Mechanistically, intercellular transfer of microRNAs (miR-522-3p and miR-454-3p) by exosomes disseminated gefitinib resistance through activating PI3K/AKT and MEK/ERK signaling pathways

      Conclusion:
      Our findings demonstrate that EGFR-TKIs resistant cells could disseminate drug resistance to sensitive cells by intercellular transfer of exosome-transmitted microRNAs and then activating PI3K/AKT and MEK/ERK signaling pathways, which reveals a novel mechanism of acquired resistance to EGFR-TKIs in NSCLC.

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    P1.03 - Chemotherapy/Targeted Therapy (ID 689)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 2
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      P1.03-045 - HER-2 Mutation Is Not a Prognostic Factor Treated with First-Line Chemotherapy in NSCLC Patients (ID 10386)

      09:30 - 16:00  |  Author(s): C. Zhao

      • Abstract

      Background:
      Human epidermal growth fator2 (HER-2) is a driver gene in non-small cell lung cancer (NSCLC), however, the effect of chemotherapy in patients with HER-2 mutation has not been studied.

      Method:
      HER-2 mutation was detected in 1041 EGFR/ALK/ROS1/KRAS/BRAF wild type NSCLC patient samples in Shanghai Pulmonary Hospital using ARMS method, and the mutation positive samples were confirmed by DNA sequencing. The clinicopathologic features and prognosis of the HER-2 mutation patients were analyzed.

      Result:
      63 samples (6.1%) were HER-2 mutation positive, and 53 samples (84.1%) were confirmed by DNA sequencing. 5(7.9%) were point mutation and 58(92.1%) were insertion mutations with 33 (52.4%) A775_G776insYVMA. Patients with A775_G776insYVMA mutation had no association with other mutations in sex, age, smoking status, and pathological types, as well as in objective response rate (ORR, 40.0% vs 28.6%, p=1.000) and progression-free survival (PFS, p=0.069). Patients with six gene wild type were matched with the 63 HER-2 mutation patients in clinicopathologic features. We found that there was no significant difference between HER-2 mutation and wild type patients in ORR (30.4% vs 29.3%, p=0.157) and PFS (7.0month vs 4.5month, p=0.086), although the PFS was longer in HER-2 mutation patients.

      Conclusion:
      HER-2 mutation was 6.1% in EGFR/ALK/ROS1/KRAS/BRAF wild type NSCLC patients. There was no significant difference between HER-2 mutation and wild type patients in ORR and PFS treated with first-line chemotherapy. Target therapy maybe needed to treat these patients.

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      P1.03-052 - Comparing EGFR-TKI with EGFR-TKI plus Chemotherapy as 1st Line Treatment in Advanced NSCLC Patients with Both Mutated EGFR and Bim Polymorphism (ID 10516)

      09:30 - 16:00  |  Author(s): C. Zhao

      • Abstract
      • Slides

      Background:
      Not all advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutations could get benefit from 1[st] line treatment of EGFR tyrosine kinase inhibitors (TKIs). Our previous study indicated that B-cell chronic lymphocytic leukemia/lymphoma-like 11 (Bim) deletion polymorphism was about 10% and was significantly associated with a poor clinical response to EGFR-TKIs in EGFR mutation-positive NSCLC. This retrospective study compared efficacy and tolerability of the EGFR-TKI alone versus EGFR-TKI plus chemotherapy as the 1[st] line treatment in advanced NSCLC patients with both activated EGFR mutation and Bim polymorphism.

      Method:
      Main included criterias were patients older than 18 years, histologically confirmed stage IIIB or IV NSCLC, EGFR mutation-positive (exon 19 deletion or 21 L858R mutation) and Bim polymorphism. Patients received gefitinib 250mg orally a day or gefitinib together with up to 4 cycles of pemetrexed/gemcitabine and platinum until disease progression or unacceptable toxic effects. The primary endpoint was progression-free survival (PFS); the second endpoint included objective response rate (ORR), overall survival (OS) and toxicity.

      Result:
      From June 2014 to September 2016, 65 patients were enrolled into this trial. 36 of them received gefitinib, and 29 received gefitinib plus pemetrexed/gemcitabine and platinum. Median PFS was significantly longer in EGFR-TKI plus chemotherapy-treated patients than in EGFR-TKI (7.2 [95% CI 5.35-9.05] vs 4.6 [4.01-5.19] months; p=0.008). The ORR was significantly lower in EGFR-TKI than in EGFR-TKI plus chemotherapy-treated patients (38.9% vs. 65.5% p=0.046). EGFR-TKI plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKI (8 neutropenia, 4 thrombocytopenia vs. no any event). Figure 1



      Conclusion:
      Compared with EGFR-TKI, EGFR-TKI plus chemotherapy conferred a significant higher ORR and longer PFS in advanced NSCLC patients with both activated EGFR mutation and Bim polymorphism. An open-label, multicenter, randomized, phase 2 study is ongoing to validate these results in our institute ( NCT03002844).

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.01-067 - TP53 Mutations Could Involved in EGFR-TKI Primary Resistance in Advanced Non-Small Cell Lung Cancer (ID 10437)

      09:30 - 16:00  |  Author(s): C. Zhao

      • Abstract

      Background:
      Activating mutations in the epidermal growth factor receptor (EGFR) are strongly predictive of EGFR-tyrosine kinase inhibitor (TKI) activity in non-small cell lung cancer (NSCLC). However, primary resistance to EGFR-TKIs occurs in approximately 20-30% of NSCLC patients with EGFR mutations, acquired resistance is inevitable. The aim of study is to discover unknown resistant mechanisms and contribute to more precisely administrate advanced and metastatic NSCLC with EGFR mutations.

      Method:
      60 NSCLC patients with EGFR sensitive mutation were enrolled this study. All of patients received EGFR-TKI treatment. 21 of patients were primary resistance and 39 acquired resistance according to Jackman standard. Tumor tissues of all of patients were collected before EGFR-TKIs treatment, and rebiopsy tissues were gained after acquired resistance in 39 NSCLC patients. Whole exome sequencing were performed in Illumina HiSeq2000 platform. The captured sequencing data was further processed to identify somatic mutations, including single nucleotide variants (SNVs), short insertions/deletions (indels) and copy number variations (CNVs).

      Result:
      In primary resistance patients, 13 patients occurred rapid progress (PFS ≤60 days) were put into group 1, and other 8 patients with PFS within 90-180 days were into group 2; in acquired resistance patients, 9 patients were observed long-term clinical benefit (PFS≥540 days) were into group 3; remaining 30 patients with PFS between 180 to 540 days were into group 4. Median PFS were 29, 95, 761 and 311 days from group 1 to 4, respectively. More signaling pathways were activated in group 1, relative to other groups, including bypass activation, downstream signal activation, apoptotic pathways disturbance and EMT activation. Meanwhile, the activation of more signaling pathways were found in samples after acquired resistance compared with paired baseline samples. In all of baseline samples, 60.0% patients harbored TP53 mutations, and these mutations distributed in exon 2,4,5,6,7,8 and 11, respectively. Interestingly, TP53 mutations of 23% patients were in exon 6 in group 1, mutations in exon 5 occurred in 33.3% patients with long-term clinical benefit (group 3). Patients with exon 6 mutation had more shorter PFS than those with exon 5 mutation (105 days vs 284 days).

      Conclusion:
      For patients resistant to EGFR-TKI, more signal pathways were activation, and the heterogeneity of tumor cloning were complicated. TP53 mutations in different exons may have distinct effect on response to EGFR-TKI of patients with EGFR sensitive mutation.