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Renhua Guo



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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-105 - Lung Cancer Patients with Concurrent EGFR and MET Mutations: A Retrospective Analysis of 29 Cases (ID 12864)

      16:45 - 18:00  |  Author(s): Renhua Guo

      • Abstract
      • Slides

      Background

      It has been reported that about 5%-20% of EGFR-TKIs resistant NSCLC patients harbors MET amplification or activating mutations. However, the extent that MET abnormal activation contributes to EGFR-TKIs resistance remains widely unknown. Here, we describe the clinical and genetic characteristics of 29 lung cancer patients harboring concurrent EGFR and MET mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Genetic mutations were reviewed in 6000 lung cancer patients who underwent genetic testing at our institute from 2016 to 2018. Mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (range 59 – 1021 genes).

      4c3880bb027f159e801041b1021e88e8 Result

      The selected patients included 24 lung adenocarcinoma patients, 1 squamous cell lung cancer patient and 3 lung cancer patients with unspecified pathology. Both MET amplification and activating mutations were included for analysis. MET amplification was detected in 90% (27/30) of samples, while activating mutations was present in 13.3% (4/30) of samples, including H1112Y, D1228N, D1246Y and D1246H. 14% (4/29) of patients had not received EGFR-TKIs treatment before genetic testing, which were considered as primary resistance. 79% (23/29) of patients were treated with EGFR-TKIs. Surprisingly, 60% (18/30) of cases had other functional mutations which may also affect the effectiveness of EGFR-TKIs, such as EGFR T790M mutation (3 cases), rare EGFR mutations (I744M, R108K and C769S, 3 cases), EGFR amplification (7 cases), CDK4 amplification (2 cases), loss-of-function mutations of CDKN2A (2 cases) and so on. One patient had two samples tested. He was resistant to gefitinib and osimertinib, and EGFR L858R mutation and MET amplification were detected in the first sample. Later, he was treated with combined gefitinib and crizotinib and reached PR at the 2nd month. However, his disease finally progressed probably due to an additional MET mutation (D1246Y) that caused resistance to crizotinib.

      8eea62084ca7e541d918e823422bd82e Conclusion

      MET amplification and activating mutations may lead to primary and acquired resistance of EGFR-TKIs. Moreover, additional potentially resistant mechanisms were detected in most cases. Therefore, it is apparently requisite to provide a comprehensive genetic testing to lung cancer patients.

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      P1.01-27 - Influence of EGFR-TKIs Treatment Lines and PFS on the Emergence of T790M Mutation (ID 13584)

      16:45 - 18:00  |  Author(s): Renhua Guo

      • Abstract
      • Slides

      Background

      For sensitizing EGFR mutation positive lung cancer patients, EGFR-TKIs can be used as the first-line or second-line (after chemotherapy) therapy according to NCCN guideline. However, whether different lines of EGFR-TKIs therapy or different PFS would affect the emergence of T790M, the leading cause of resistance to first and second generation of EGFR-TKIs was unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed 142 advance NSCLC patients with 93 patients received 1st-line EGFR-TKIs, and 49 patients received 2nd-line EGFR-TKIs after chemotherapy. EGFR sensitizing mutation and T790M mutation was detected simultaneously by hybridization capture-based NGS panel sequencing with tumor biopsy , ctDNA or pleural effusion samples.

      4c3880bb027f159e801041b1021e88e8 Result

      For the patients received 1st-line EGFR-TKIs, 47 carried L858R mutation and 46 carried EX19del mutation; while patients received 2nd-line EGFR-TKIs, 24 carried L858R mutation and 25 carried EX19del mutation. When those patients progressed on TKIs, T790M emerged in 25 of the 47 (53.19%) L858R carriers, and 23 of the 46 (50.00%) EX19del carriers with 1st-line EGFR-TKIs (p=0.76). However, only 6 of the 24 (25.00%) L858R carriers yet 16 of the 25 (64.00%) EX19del carriers with 2nd-line EGFR-TKIs had T790M detected (p=0.006). The incidence of T790M was significant lower in L858R carrier treated with 2nd-line compared with 1st-line EGFR-TKIs (25.00% vs 53.19%, p=0.023), however, there was no difference for EX19del carrier (50.00% vs 64.00%, p=0.26). To further analyzed whether different PFS affected the appearance of T790M, we divided patients into 3 groups as PFS≥13 months (n=48), PFS≤8 months (n=60) and the between (n=34). The incidence of T790M was significantly lower in the PFS≤8 months group compared with the PFS≥13 months (31.67% vs 62.5%, p=0.001). The difference was also significant if only counting the L858R carriers (18.52% vs 59.26%, p=0.002), but not significant in the EX19del carriers (42.42% vs 66.67%, p=0.082).

      8eea62084ca7e541d918e823422bd82e Conclusion

      1st-line or 2nd-line EGFR-TKIs generally did not significantly alter the emergence of T790M. But for the L858R mutation carriers, the incidence of T790M is significantly decreased if treated as a 2nd-line EGFR-TKIs therapy. In addition, patients with longer PFS were associated with higher incidence of T790M mutation.

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      P1.01-62 - The Third Generation Irreversible EGFR Inhibitor HS-10296 in Advanced Non-Small Cell Lung Cancer Patients (ID 13138)

      16:45 - 18:00  |  Author(s): Renhua Guo

      • Abstract
      • Slides

      Background

      The epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism of drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The third generation irreversible EGFR inhibitor HS-10296 has been shown to be safe and effective against both EGFR TKI-sensitizing and T790M resistance mutations in preclinical studies.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A Phase I, open-label, multi-center clinical trial was conducted in patients with locally advanced or distant metastatic NSCLC who have progressed following prior therapy with EGFR TKIs. The study was consisted of dose-escalation cohorts (55, 110, 220 and 260 mg) and dose-expansion cohorts (55, 110 and 220 mg) with once daily oral administration of HS-10296. In each expansion cohort, tumor biopsies were collected for central determination of EGFR T790M status. Patients were assessed for safety, tolerability, pharmacokinetics and efficacy of HS-10296.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 117 patients (median age 60) received at least one dose of HS-10296 across multiple sites in China (43 patients), Taiwan (69 patients) and the United States (5 patients). Maximum tolerated dose(MTD)has not been reached in this study. The most common adverse events were grade1/2 rash, pyrexia, upper respiratory tract infection, constipation, diarrhoea and blood creatine phosphokinase elevation. Drug-related serious adverse events were anemia (0.8%), blood creatinine elevation (0.8%), anemiarhabdomyolysis (0.8%) and blood creatine phosphokinase elevation (0.8%) occurred mainly in the cohorts with higher doses at 220 mg or 260 mg, respectively. These data demonstrated favorable tolerability and safety of HS-10296 in patients enrolled. The pharmacokinetics of HS-10296 was dose proportional and the plasma half-life was 30.7~37.5 hours. Among 82 evaluable patients (18 in escalation cohorts and 64 in expansion cohorts) with the EGFR T790M mutation, the overall objective response rate (ORR) was 52.4% (43/82; 95% CI, 41.6 to 63.3), while disease control rate (DCR) was 91.5% (75/82; 95% CI, 85.4 to 97.5). 110mg cohort showed better DCR (97.2% VS. 86.1%) than 55mg cohort. Phase II study is ongoing with the dose at 110 mg.

      8eea62084ca7e541d918e823422bd82e Conclusion

      HS-10296 has the potential to provide clinical benefit to locally advanced or distant metastatic NSCLC patients with EGFR T790M mutation who had disease progression following prior therapy with EGFR TKIs.

      (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

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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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      P1.13-08 - Distribution, Differences in Clinical Characteristics and Resistance Mechanism of ALK Variants in Chinese Lung Cancer Patients. (ID 13678)

      16:45 - 18:00  |  Author(s): Renhua Guo

      • Abstract
      • Slides

      Background

      ALK rearrangements are established targetable drivers in NSCLC. Recent reports indicate differential progression-free survival to ALK inhibitors according to specific EML4-ALK variant.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 172 unique Chinese lung cancer patients with tumors harboring ALK rearrangements (ALK+) were enrolled in the study from 2016 to 2018. ALK+ were detected by Ventana, FISH, or next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations across at least 59 genes (59-1021). Tissue biopsy was the first choice for NGS mutation profiling, and ctDNA or pleural effusion testing was used as an alternative.

      4c3880bb027f159e801041b1021e88e8 Result

      Of these 172 cases, the median diagnosis age was 50 (range 24-78), 58% were female, 90% was NSCLC. Of the 147 ALK+ cases detected by NGS, we identified 65 (44%) EML4-ALK v1 (E13; A20), 18 (12%) EML4-ALK v2 (E20; A20), 43 (29%) EML4-ALK v3 (E6; A20), 13 (9%) other EML4-ALK, and 8 (5%) non-EML4-ALK rearrangements. 2 new fusion genes were found in non EML4-ALK rearrangements (SRBD1-ALK (EX20; EX20) and CLIP4-ALK (EX9; EX20)), and the CLIP4-ALK patient’s tissue was also ALK positive by Ventana. V1 found a higher proportion of pleural effusion at baseline than non-v1 (12% v.s.5%). Mutation profiling by NGS were performed after disease progression in 55 patients treated with crizotinib. mPFS was 8.1 months, no significant difference existed between v1 and v3 (P=0.69). But the presence of known ALK resistance mechanisms was significantly higher in v3 as compared to non-v3 (67% v.s. 27%, P=0.038).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Next generation sequencing allows for detection of the specific ALK fusion partner and variants, increases the understanding of the biology of ALK+ NSCLC, and may have value to foretell potential mechanisms of resistance.

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 4
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-107 - Analysis of Mutation Detection by ctDNA on the Basis of Metastatic Sites in Lung Adenocarcinoma Patients (ID 13635)

      16:45 - 18:00  |  Presenting Author(s): Renhua Guo

      • Abstract

      Background

      Circulating tumor DNA (ctDNA) testing represents a powerful tool to detect gene alterations in patients. However, differences in mutation detected by ctDNA related to metastatic sites in lung cancer have not been addressed before and remain to be explored.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed 317 ctDNA samples from 310 lung adenocarcinoma patients with definite metastasis at our institute. Somatic mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of 1021 genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients were divided into two groups according to metastatic sites. Any case with metastasis to the bone, liver or adrenal gland falls into the major organ metastasis group, while any case with metastasis to the lung, pleura or lymph node belongs to the local metastasis group. No genetic alteration was detected in 14 (11.5%) of 122 samples in the major organ group and 35 (17.9%) of 195 in the local group. And distant metastasis is associated with more mutations on average detected by ctDNA (5.26 for the major organ group vs 3.72 for the local group; p=0.0039). As for genes involved, the most common mutated ones are EGFR and TP53 for both groups, with an overall mutation rate being 40.6% and 33.2% respectively. And just as average gene alterations mentioned above, the mutation rates of EGFR and TP53 are much higher in the major organ group (49.6% vs 35.2% for EGFR; 43.6% vs 26.9% for TP53). Besides, mutations of NF1, MLL3, KRAS and KEAP1 are more frequent in the major organ group while mutation rate of PIK3CA is slightly higher in the local group (Table).

      Table. Some mutated genes detected by ctDNA

      major organ metastasis (117)

      local metastasis (193)

      EGFR

      58 (49.6%)

      68 (35.2%)

      TP53

      51 (43.6%)

      52 (26.9%)

      KRAS

      9 (7.7%)

      7 (3.6%)

      MLL3

      9 (7.7%)

      6 (3.1%)

      NF1

      9 (7.7%)

      3 (1.6%)

      ERBB2

      5 (4.3%)

      6 (3.1%)

      PIK3CA

      3 (2.6%)

      7 (3.6%)

      KEAP1

      7 (6.0%)

      3 (1.6%)

      8eea62084ca7e541d918e823422bd82e Conclusion

      More gene alterations were detected by sequencing of ctDNA in patients of lung adenocarcinoma with major organ metastasis compared to those with only local metastasis.

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      P2.01-117 - Concurrent Gene Alterations in Treatment-Naïve EGFR-Mutant Advanced Non-Small Cell Lung Cancer (ID 13102)

      16:45 - 18:00  |  Author(s): Renhua Guo

      • Abstract
      • Slides

      Background

      EGFR-TKIs is the standard first line treatment for EGFR-mutant advanced non-small-cell lung cancer (NSCLC). However, 20% to 30% of patients who receive EGFR-TKIs exhibit primary resistance. The gene alterations in treatment-naïve EGFR-mutant advanced NSCLC should be better explored.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed gene test results of 980 treatment-naïve advanced NSCLC samples in our institute. Tumor biopsy, ctDNA, pleural effusion or cerebrospinal fluid samples were analyzed using hybridization capture-based NGS ER-seq method, white blood cells as control, which enables simultaneously assess single-nucleotide variants (SNV), insertions/deletions (indel), rearrangements and somatic copy-number(CNV) variation at least 59 genes (range 59-1021 genes).

      4c3880bb027f159e801041b1021e88e8 Result

      Three hundreds and eighty one cases with EGFR sensitive mutation were identified, 358 adenocarcinoma, 7 squamous cell carcinoma, 1 adenosquamous carcinoma and 15 NSCLC. Among the patients, 88 patients (23.1%) harbored concurrent actionable mutations with EGFR, which 43 were exon 19 deletion, 37 were L858R and 8 were uncommon EGFR mutations. One patient had co-occurring L858R, T790M and CDKN2A frameshift mutation. The actionable mutations were from 23 genes, which involved in cellular signaling pathways, and some genes had been reported associated with EGFR-TKIs resistance (details in table). Except the actionable mutations, TP53 mutations were detected in 225 samples (59.1%, 225/381), which 35.1% (79/225) in exon8. Bcl-2–like 11(BIM) deletion were detected in 31 (8.1%, 31/381) white blood cells.

      Signaling Pathways

      Concurrent gene alterations

      Frequency(N=88)

      Cell cycle*

      CDKN2A

      3.9%

      CDK4

      2.1%

      CCNE1

      0.8%

      CCND1

      0.8%

      CCND3

      0.3%

      PI3K/AKT/mTOR*

      PIK3CA

      2.9%

      PTEN

      1.3%

      TSC1/2

      1.0%

      AKT2

      0.3%

      NF1

      0.3%

      RTKs*

      MET

      0.8%

      HER2

      0.8%

      FGFR2

      0.3%

      FGFR3-TACC3

      0.3%

      Ras/Raf/MAPK*

      KRAS

      0.8%

      Homologous Recombination Repair pathway

      BRCA2(sc+gm)

      0.8%

      BRCA1(sc)

      0.5%

      ATM

      0.5%

      PALB2

      0.3%

      Others

      CTNNB1

      2.9%

      MDM2

      2.4%

      SMARCA4

      0.8%

      JAK2

      0.5%

      sc, somatic mutation;

      gm, germline mutation;

      *, genes had been reported associated with EGFR-TKIs resistance

      8eea62084ca7e541d918e823422bd82e Conclusion

      Concurrent gene alterations in treatment-naïve EGFR-mutant advanced NSCLC is common, and mutiple genes are involved. This maybe contribute to the primary resistance to EGFR-TKIs in EGFR-mutant advanced NSCLC. Indicate the importance of multiplex molecular test and further researches of target therapies.

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      P2.01-44 - Prognostic Value of TP53 Hot Exon Mutation in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 13150)

      16:45 - 18:00  |  Author(s): Renhua Guo

      • Abstract
      • Slides

      Background

      Numerous studies have revealed either very marginal or no prognostic value of TP53 mutation NSCLC patients. Currently, in clinical settings, all TP53 mutations have been considered equally, without any differentiation between the various types and positions of mutations. However, increasing evidence has triggered us to challenge such practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively investigated the correlation between mutations occurring at hot exons (5-8) and overall survival (OS) in 214 previously tyrosine kinase inhibitor (TKI) treated advanced NSCLC patients. Among them, 184 had 1 line of TKI-treatment and the remaining 30 patients had more than 1 line of TKI-treatment. 115 harbored TP53 mutation; among them 105 patients had concurrent EGFR mutation; 5 had ALK rearrangements; 1 had ROS1 rearrangements; 1 had KRAS and 2 had ERBB2 mutations. 99 patients had wild type (WT) TP53; among them, 92 had EGFR mutation, 4 with ALK-rearrangements, 1 with MET and 1 with BRAF mutation. Fisher’s exact test and the Mann-Whitney test were used to determine if categorical and continuous variables, respectively, differed between TP53 WT and mutant groups.

      4c3880bb027f159e801041b1021e88e8 Result

      The prevalence of TP53 mutation in our cohort is 53.7% (115/214); 28 had mutation on exon 5, 18 on exon 6, 22 on exon 7 and 32 on exon 8. 32 patients had loss of function mutation and 51 patients had disruptive mutation. Our data revealed a positive correlation with N and M stage. Patients harboring TP53 mutation are more likely to diagnose with more advanced N (p=0.018) and M stage (p=0.001). Furthermore, patients with TP53 mutation are more likely to have liver (p<0.001) and bone metastasis (p=0.012). In patients treated with only 1 line of TKI-treatment, although TP53 status had no effect on PFS (p=0.241) and OS (p=0.49) when they were considered collectively, we observed patients with mutation in exon 5 had shorter OS (p=0.029) and mutation in exon 8 had shorter PFS (P=0.003) after controlling for age, gender, stage and histology. Furthermore, within the osimertinib subgroup (N=101), patients harboring mutation in exon 8 had significantly shorter PFS (P=0.007). In patients treated with more than 1 line of treatment, neither TP53 mutation considered collectively, nor hot exon mutations had correlation with PFS or OS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study revealed unfavorable prognostic value of mutations in exon 5 and no prognostic value of TP53 if all mutations were considered collectively. Our study adds new dimension to the emerging picture that not all TP53 mutants are equal.

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      P2.01-69 - EZH2-Mediated Epigenetic Suppression Of GDF15 Predicts a Poor Prognosis and Regulates Cell Proliferation in Non-Small Cell Lung Cancer (ID 12457)

      16:45 - 18:00  |  Author(s): Renhua Guo

      • Abstract
      • Slides

      Background

      Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily of cytokines, has been reported to exert very heterogeneous functions in various tumors. However, the role of GDF15 and its underlying mechanism in mediating non-small cell lung cancer (NSCLC) progression remain unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      GDF15 expression level was analyzed in 66 NSCLC tissues by quantitative reverse transcription PCR (qRT-PCR). The effect of GDF15 on proliferation was evaluated by MTT and colony formation assays, flow cytometric analysis. NSCLC cells transfected with pcDNA-GDF15 or empty vector were injected into nude mice to study the effect of GDF15 on tumorigenesis in vivo. Chromatin immunoprecipitation (ChIP) assay was used to investigate the mechanism of action of GDF15 in the NSCLC cells.

      4c3880bb027f159e801041b1021e88e8 Result

      In this study, we found that GDF15 is down-regulated in paired NSCLC tissues and is correlated with poor clinical outcomes in NSCLC. Further experiments demonstrated that overexpression of GDF15 significantly repressed NSCLC proliferation both in vitro and in vivo. Mechanistic studies reveal that inhibition of EZH2 expression prevented its binding to the GDF15 promoter region and reduced the trimethylation modification pattern of H3K27.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Together, our data uncover that GDF15 is a direct target of EZH2, and as a regulator of proliferation, might serve as a candidate prognostic biomarker and target for new therapies in human NSCLC.

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-34 - Long Intergenic Non-Coding RNA 00665 Induces Acquired Resistance to Gefitinib in Non-Small-Cell Lung Cancer (ID 11903)

      16:45 - 18:00  |  Author(s): Renhua Guo

      • Abstract
      • Slides

      Background

      Gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI), has been used as the first choice of treatment for advanced non-small cell lung cancer (NSCLC). However, during the course of treatment cancer cells often develop resistance to gefitinib without fully understood mechanisms. In recent years, numerous studies have shown that long non-coding RNAs (lncRNAs) play vital roles in modulating various biological processes, such as cell apoptosis, proliferation, migration, and invasion. Nevertheless cancer drug resistance mechanisms related to LncRNAs and their important roles in cancer development are still poorly understood. In this study, we aimed to elucidate an important role of long intergenic non-coding RNA 00665 (LINC00665) in developing resistance to gefitinib in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Quantitative reverse transcription PCR (qRT-PCR) was performed to examine the expression levels of LINC00665 in 10 pairs of LUAD tissues from patients who had never been treated with gefitinib (NG) and those who were treated with gefitinib but developed resistance (GR). The effect of LINC00665 on proliferation and apoptosis in gefitinib-resistant cells was evaluated by CCK8, colony formation, flow-cytometric analysis and in vivo tumor formation assays. Western-blot and immunohistochemistry were used to evaluate the expression of EGFR and its downstream event.

      4c3880bb027f159e801041b1021e88e8 Result

      LINC00665 expression levels were significantly increased in NSCLC patients who developed acquired resistance to gefitinib compared to the NG group.Furthermore, LINC00665 inhibition reversed gefitinib sensitivity both in vitro and in vivo by suppressing cell growth and induced cell apoptosis. Importantly, knockdown of LINC00665 marked decreased activation of EGFR and its downstream event Akt and ERK1/2.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Taken together,our study demonstrates that LINC00665 may be a potential biomarker of response to gefitinib as well as a novel therapeutic target for future treatment of NSCLC.

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