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Xueqin Chen
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EP1.03 - Biology (ID 193)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.03-16 - Lysimachia Capillipes Capilliposide C Restores Radiation Sensitivity in Radiation Resistant Lung Cancer Cells by Enhancing ERRFI1 Expression (ID 810)
08:00 - 18:00 | Author(s): Xueqin Chen
- Abstract
Background
Radiation therapy is used as the primary treatment for lung cancer. Unfortunately, radiation resistance and local failure remain to be the major clinic problems for lung cancer patients. It is therefore crucial to find new therapeutic targets and/or drugs to enhance the effects of radiation without increasing the adverse effects. Lysimachia capillipes capilliposide C (LC-C) extracts from LC Hemsl. show anti-cancer effects both in vitro and in vivo. The purpose of this study is to investigate a potential therapeutic impact of LC-C as a radiation sensitizer in lung cancer cells.
Method
Non small cell lung cancer (NSCLC) cell line A549 was initially irradiated with a total dose of 60 Gy (3 Gy/Fx, 20 Fx, 2-3 Fx/week) to generate radiation-resistant cancer cell line A549-IR. RNA-seq analysis was used to examine the whole-transcriptome alteration in A549-IR cells treated with or without LC-C, and the differentially expressed genes with most significance were verified by RT-qPCR. Colony formation assays were performed to determine the effect of the target gene ErbB receptor feedback inhibitor 1 ( ERRFI1) on radiosensitivity of A549-IR cells. In addition, effects of ERRFI1 on cell cycle distribution, DNA damage repair activity were assessed by flow cytometry and γ-H2AX immunofluorescence staining respectively. Western blot was performed to identify the activation of related signaling pathways. Tumor xenograft experiments were conducted to observe the effect of LC-C and ERRFI1 on radiosensitivity of A549-IR cells in vivo.
Result
ERRFI1 was significantly up-regulated in A549-IR cells when cells were treated with LC-C (IC20=3.5 μM). With irradiation treatment, clonogenic formation decreased in the ERRFI1 overexpressed cells when comparing to the parental cells, with reduced survival fraction-2 value from 0.54±0.07 to 0.24±0.06 (p<0.01). The sensitizing enhancement ratio for LC-C was 1.667. Furthermore, ERRFI1 overexpression may enhance radiosensitivity of A549-IR cells in vitro by inducing G2/M phase arrest and inhibiting DNA damage repair. Overexpression of the ERRF11 decreased the activation of EGFR and STAT3 signaling pathways in A549-IR cells. Knocking down ERRFI1 expression in A549-IR cells attenuated the radiosensitization effect of LC-C. Moreover, in a A549-IR cells-derived xenograft model, combination treatment with LC-C (25 mg·kg−1·d−1, qod, ig) and irradiation (6Gy) dramatically enhanced tumor growth suppression comparing with LC-C or radiation alone.
Conclusion
LC-C can restore the cells' sensitivity to irradiation through regulation of ERRFI1 expression in lung cancer cells. Combination treatment of LC-C and irradiation may serve as a promising therapeutic strategy to overcome the radiation resistance and ERRFI1 may be a poteintal therapeutic target to improve radiosensitivity in NSCLCs.
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EP1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 206)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.16-22 - Pemetrexed, Platinumin Combination with Bevacizumab for Chinese Patients with Advanced Lung Adenocarcinoma Cancer: A Real World Study (ID 2369)
08:00 - 18:00 | Presenting Author(s): Xueqin Chen
- Abstract
Background
Bevacizumab and platinum based chemotherapy have been standard treatment for advanced non-squamous non-small cell lung cancer. Otherwise, the chemotherapy protocol is often paclitaxel and carboplatin, and pemetrexed combination with platinum are also generally used in our clinical practice. Thus, the aim of this present study is to evaluate the efficacy and safety of cisplatin or carboplatin+pemetrexed combination with bevacizumab followed by maintenance pemetrexed and bevacizumab for Chinese chemotherapy-naïve patients with advanced lung adenocarcinoma cancer in real word.
Method
A total of 44 chemotherapy-naïve patients with advanced lung adenocarcinoma cancer were administered pemetrexed (500 mg/m2), cisplatin(60mg/m2)/carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to six cycles. Maintenance PB was administered until disease progression or unacceptable toxicity. The endpoints were objective response rate (ORR), progression-free survival (PFS) and safety.
Result
44 advanced lung adenocarcinoma cancer patients were enrolled and median age was 61 years. 33 patients were males, 24 were never smokers, the ECOG performance status of 42 patients were 0 and 1. The status of epidermal growth factor receptor mutation, ALK and ROS1 fusion were all negative in 26 patients. EGFR mutation, ALK or ROS1 fusion positive and unkown were 10, 2 and 6 patients respectively. The median cycles of induction therapy and maintenance were 4.2 (95% confidence interval, 2-7) and 3.7 (95% confidence interval, 0-22).The median PFS was 7.4 months. The ORR, SD and DCR were 63% , 32 % and 95% respectively. The grade 3 or 4 toxicities were neutropenia (8%), anemia (1%), fatigue (1%).
Conclusion
The combination of the bevacizumab, pemetrexed, and platinum demonstrated activity with acceptable toxicity in patients with advanced lung adenocarcinoma cancer regardless of drive gene status.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-19 - Predictive and Prognostic Values of ctDNA Clearance in Osimertinib Treated Advanced Non-Small Cell Lung Cancer Cohort (Now Available) (ID 2061)
09:45 - 18:00 | Author(s): Xueqin Chen
- Abstract
Background
Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at the molecular level. Circulating tumor DNA (ctDNA), validated as a tool for mutation detection in lung cancer, reflects dynamic molecular changes. Here, we evaluated the potential of ctDNA in monitoring molecular changes and predicting clinical outcomes of EGFR T790M-positive osimertinib treated NSCLC patients.
Method
This prospective multicenter study, enrolled 72 T790M positive osimertinib-treated advanced NSCLC patients who progressed on prior EGFR-TKI to evaluate the potential of ctDNA in monitoring, is part of the ongoing ASTRIS study (NCT02474355). Longitudinal plasma samples, collected from 52 patients, were subjected to sequencing using a panel consisting of 168 lung cancer-related genes.
Result
Genomic profile prior to the initiation of osimertinib revealed that mutations participating in cell cycle (14 patients, p=0.004) and P53 pathways (43 patients, p=0.032) were associated with shorter OS (p53 was excluded from analysis due to high mutation frequency). Interestingly, patients with undetectable ctDNA at first follow-up (within 50 d, n=41) were correlated with longer PFS (p=0.009) and OS (p=0.022). With a median follow-up of 168 d (ranged from 40 - 550 d), 32 patients experienced radiological disease progression. Among them, 11 (34%) experienced molecular progression reflected by emergency of new mutation or increased allelic frequency of existing mutation prior to radiological progression, with an average leading time of 74 days. Patients with molecular PD prior to radiological PD were more likely to harbor any gene copy number amplification (CNA, p=0.035) and p53 (p=0.023) mutations at radiological PD. In addition, patients with CNA at radiological PD had shorter PFS (p=0.002) and OS (p=0.052).
Conclusion
This clinical trial study demonstrates that ctDNA clearance at first follow-up can serve as a predictive and a prognostic marker for patients undergoing osimertinib treatment. Furthermore, it revealed the potential of ctDNA in early detection of disease progression, preceding imaging modalities with an average lead time of 74 days.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-51 - LOC440416 lncRNA-Mediated Cell Cycle Arrest Regulated Crizotinib-Induced Hepatotoxicity (ID 1073)
09:45 - 18:00 | Presenting Author(s): Xueqin Chen
- Abstract
Background
To evaluate crizotinib-induced hepatotoxicity in mice and investigate the role of cell cycle arrest mediated by LOC440416lncRNA during liver injury, furthermore, to provide experiment evidence for screening available hepar protector and expending the clinical application of crizotinib.
Method
The levels of blood serum ALT, AST, LDH were detected using ICR mouse model. Liver samples of mouse fixed were stained with hematoxylin and eosin for histopathological analysis. The cell inhibition rate of primary hepatocytes was detected by MTT assay.Cell cyclin distribution was detected by flow cytometry(FCM) and the expressions of cell cycle protein cyclinB1 and CDK1 were detected with Westblot after mouse primary hepatocytes were treated with 2.5 µM, 5µM, 10 µM crizotinib for 48h. Apoptosis was evaluated by DAPI staining and PI staining for flow cytometry and the expressions of cell apoptosis protein c-PARP and c-caspase-3 were detected with Westblot. LncRNAs regulating hepar cell cycle arrest were screened using Microarray Chip technique after primary hepatocytes were treated with 5μM crizotinib for 24h. The expressions of cell cyclin protein cyclin B1 and CDK1 were tested with Westblot, after siRNA gene silencing technology was used to knock down LOC440416lncRNA.
Result
The levels of blood serum ALT, AST, LDH elevated significantly in mice after crizotinib treatment．Slices of liver by HE staining for analysis showed cellular swelling of hepatocytes, nucleolus staining deepened and karyokinesis phenomenon with inflammatory cell infiltrate. In vitro, MTT assay showed crizotinib-induced hepatotoxicity in mouse primary hepatocytes presented dose-dependented and IC50 value was 4.6μM. DAPI staining exhibited clear chromatin condensation, fragment and apoptotic bodies and FCM showed sub-G1 apoptosis peak was formed after 5μM and10 μM crizotinib treatment. Westblot demonstrated caspase-3 activation and PARP cleavage. All these data revealed that crizotinib-induced hepatotoxicity was through the process of apoptosis. FCM showed the population of G2/M phase elevated, these of G0/G1 phase decreased and G2/M arrested while the concentration of crizotinib was increased. Reduced protein levels of Cyclin B1 and increased protein level of CDK1 were also observed with Westblot. After crizotinib treatment, sixteen elevated or decreased lncRNAs were found more than ten times separately by terms of Microarray Chip technique. LOC440416lncRNA regulating cell cycle arrest was screened by Real-time PCR. The restoration of reduced Cyclin B1, increased CDK1 expressions, even if hepatocytes were treated with crizotinib, after siRNA gene silencing technology was used to knock down LOC440416lncRNA.
Conclusion
Crizotinib-induced hepatotoxicity was demonstrated by experiment in vivo and in vitro. Cell cyclin G2/M check point arrest accompanied with decreased expression of cyclin B1 protein and increased expression CDK1, mediated by LOC440416 lncRNA , could be the possible mechanism.
