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W. Zhang
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-021 - Crizotinib Efficacy in ALK-Positive Advanced NSCLC Chinese Patients (ID 261)
09:30 - 09:30 | Author(s): W. Zhang
- Abstract
Background:
Anaplastic lymphoma kinase (ALK) is a new tyrosine kinase target that has been validated recently in NSCLC. Crizotinib, an oral, small-molecule, tyrosine kinase inhibitor that targets ALK, MET and ROS-1, has been reported to be particularly effective and to have acceptable toxicity in advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). In a phase 1, open-label, multicenter trial evaluating the efficacy and adverse event profile of crizotinib in a cohort of 82 ALK-positive lung cancer patients, treatment for a mean duration of 6.4 months achieved an overall response rate (ORR) of 57%, and the estimated probability of 6-months’ progression-free survival (PFS) was 72%. Mild gastrointestinal disturbances were the main adverse effects observed in this study. Subsequently, updated data from a study involving 143 patients confirmed the durable response and tolerable adverse effect profile of crizotinib in patients with ALK-positive NSCLC.
Methods:
A total of 72 patients with ALK-positive NSCLC who received crizotinib between June 1, 2013 and October 15, 2014 at Shanghai Chest Hospital, Shanghai JiaoTong University, were prospectively enrolled in the study. All were histologically diagnosed and staged as clinically advanced (stage IV, or stage IIIB with pleural effusion) NSCLC. All patients received oral crizotinib 250 mg twice daily in 28-day cycles. The tumor response was assessed after the first cycle of crizotinib therapy and subsequently after every 2 cycles using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Tolerability was assessed at least twice per cycle until crizotinib was discontinued.
Results:
The patients tended to be young (mean age 55 years, range 31-83 years), never or light smokers (smoking index <400), and to have an adenocarcinoma histology. Most (49/72; 68.1%) had received previous anticancer treatment before crizotinib therapy. Sixty-seven patients (93%) were able to be assessed for efficacy. The objective response rate (ORR) and disease control rate (DCR) were 52.2% (95% CI 40.5%-63.9%) and 64.2% (95% CI 52.75%-75.7%), respectively. The estimated median progression-free survival (PFS) for all 67 patients was 10.3 months (95% CI 8.6-12.0 months). Mild visual disturbances, nausea, vomiting, diarrhea and constipation were the most commonly reported adverse effects.Figure 1
Conclusion:
crizotinib was well tolerated and showed promising efficacy in Chinese patients with ALK-positive, advanced NSCLC. Further prospective, multicenter studies with a larger sample size are needed to confirm these findings.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-046 - MFN2 Regulates Lung Adenocarcinoma Cell Proliferation and Invasion (ID 2231)
09:30 - 09:30 | Author(s): W. Zhang
- Abstract
Background:
Mitofusin-2 gene (MFN2) encodes a mitochondrial protein which is critical for mitochondrial fusion process. MFN2 was initially identified as a hypertension-associated gene and implicated in the pathogenesis of multiple cancer types. However, roles and underlying mechanisms of MFN2 in lung adenocarcinoma development remain to be determined.
Methods:
MFN2 expression at protein level was examined in 30 pair lung adenocarcinoma/adjacent normal lung samples with immunohistochemistry staining. Then MFN2 knockdown was performed in human lung adenocarcinoma cells A549 with lentiviral-mediated shRNA strategy. The effects of MFN2 knockdown on cell proliferation, cell cycle process, cell migration and invasion was investigated in A549 cells. Then MFN2-knockdown induced gene expression changes in A549 cells was analyzed by microarray assay and then functional pathway enrichment analysis was performed to identify critical pathways involved in MFN2-mediated lung adenocarcinoma development. The expression changes of downstream factors were further determined in A549 cells by western blot.
Results:
As compared to adjacent normal lung tissues, MFN2 expression was significantly higher in lung adenocarcinoma tissues with positive MFN2 signals in 90% (27/30) lung adenocarcinoma tissues and only in 26.7% (8/30) adjacent normal tissues (Fig. 1A, B). Furthermore, MFN2 knockdown inhibited cell proliferation (Fig. 1C), induced cell cycle arrest (Fig. 1E) and blocked invasion behavior (Fig. 1D) in A549 lung adenocarcinoma cells. Microarray analysis revealed that a lot of genes were deregulated in A549 cells with MFN2 knockdown (Fig. 1F). Then functional pathway enrichment revealed six pathways were enriched in deregulated genes including Cell cycle, DNA replication, ECM-receptor interaction, Focal adhesion, MAPK signaling pathway and Chemokine signaling pathway (Fig. 1G). Furthermore, the downregulation of RAP1A and upregulation of RALB and ITGA2 identified in MFN2-knockdown cells by microarray analysis were confirmed by western blot (Fig. 1H).Figure 1
Conclusion:
Our results confirmed the involvement of MFN2 in the pathogenesis of lung adenocarcinoma and revealed that MFN2 was critical for cell proliferation and invasion in lung adenocarcinoma cell line A549. Furthermore, microarray analysis identified multiple pathways deregulated in MFN2-knockdown cells, providing valuable insights about the mechanisms underlying MFN2-associated lung adenocarcinoma development.
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P1.04-090 - Roles of MLF1IP in the Proliferation of Lung Adenocarcinoma Cells (ID 2234)
09:30 - 09:30 | Author(s): W. Zhang
- Abstract
Background:
MLF1IP was initially identified as a MLF1 interacting protein, which encodes a centromere protein essential for cell cycle and mitosis. It has been reported that MLF1IP depletion impaired the interaction between centromere and microtubules, finally inducing defects in cell mitosis. However, the involvement of MLF1IP in lung adenocarcinoma development and related mechanisms remain to be elucidated.
Methods:
MLF1IP expression at mRNA level in 15 pair lung adenocarcinoma/adjacent normal lung samples was examined with real-time PCR assay. Then the expression of MLF1IP in human lung adenocarcinoma cells A549 was inhibited with lentiviral-mediated shRNA strategy. Effects of MLF1IP knockdown on cell proliferation was analyzed by Cellomics cell counting method and MTT assay. Then the impact of MLF1IP knockdown on colony formation, cell cycle process and cell survival was determined in A549 cells by colonogenesis assay, PI staining and Annexin V-APC staining respectively.
Results:
MLF1IP expression was significantly increased in lung adenocarcinomas as compared to adjacent normal lung tissues (fold change=2.50, P<0.05), with higher MLF1IP expression observed in 66.7% (10/15) samples while lower expression observed in only 20% (3/15) samples (Fig. 1A). Furthermore, MLF1IP knockdown impaired cell proliferation (Fig. 1B, C), inhibited colony formation ability (Fig. 1D), induced cell cycle arrest (Fig. 1E) and promoted cell apoptosis (Fig. 1F) in A549 lung adenocarcinoma cells.Figure 1
Conclusion:
Our study showed that MLF1IP expression is correlated with lung adenocarcinoma development and MLF1IP expression is critical for cell proliferation and survival in lung adenocarcinoma cell line A549. MLF1IP represents a novel potential target for lung adenocarcinoma therapy.
