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MO24 - NSCLC - Chemotherapy III (ID 110)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
MO24.12 - Association between POLI polymorphism and severe gastrointestinal toxicity in non-small cell lung cancer patients in a Chinese population (ID 1087)
10:30 - 12:00 | Author(s): M. Shao
POLI is one of the Y-family polymerases, which are considered as error-prone replicases with low fidelity and involved in translesion synthesis (TLS) pathway. Polymorphisms on POLI genes may affect efficiency of DNA damage tolerant repair, therefore affect the platinum-based chemotherapy tolerance in tumor tissue and maintain routine function of normal organs. Our study aimed to investigate the association of five SNPs of POLI at codon 731, 5’-upstream and 3’UTR with prognosis and severe toxicity in advanced NSCLC patients in eastern developed regions in China.
663 stage III-IV aNSCLC patients treated with first-line platinum-based chemotherapy were genotyped with MassARRY platform on the five polymorphisms.
p.731Ala (G of rs8305) indicated protective tendency from severe grade III-IV gastrointestinal toxicity in a dominant genetic model (adjusted odds ratio for Ala/Ala+Ala/Thr: 0.51, 95% confidence internal, 0.28-0.93； P for trend = 0.028). Stratified analysis revealed that the protective effect was rather for cisplatin- than carbonplatin-based regiments (adjusted OR for Ala/Ala+Ala/Thr: 0.38, 95% CI, 0.18-0.81； P for trend = 0.012). As linked loci of rs8305, rs3730668 on 5’-upstream and rs513543 on 3’-UTR of POLI performed similar protective tendency to gastrointestinal toxicity. No significant association was discovered for these five SNPs with other hematological toxicity, progress-free survival and overall survival. Both haplotype and diplotype analysis revealed consistent result as single polymorphism analysis. Haplotype “AAA” (in the order of rs3730668-rs8305-rs513543) indicated a significant susceptibility to gastrointestinal toxicity (adjusted OR: 1.92; 95% CI, 1.19-3.10; P = 0.007).
For the first time, our study indicated error-prone replicase POLI was associated with gastrointestinal toxicity in aNSCLC patients accepting first-line platinum-base chemotherapy, especially for cisplatin-based regiments.
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P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
P3.05-006 - Inhibition of Tumor Cell Growth, Migration by SIM-89, a Novel Inhibitor of c-Met Tyrosine Kinase (ID 1112)
09:30 - 16:30 | Author(s): M. Shao
It has been found that HGF-dependent c-Met（HGFR） autocrine is activated in a wide variety of human primary and second malignancies. On the other hand, the metastatic growth potential of tumors can be activated through paracrine mechanism. c-Met dysregulation leads to lung cancer development through overexpression and mutation.
70 kinase enzymogram screening was proceeded by Z-lyte technique. MOA analysis was completed on the inhibited kinases. Cell vitality was determined at 24h, 48h, 72h after treatment through CCK8 method. Transwell system was used to observe the inhibition of cell migration. Difference of special gene expression was evaluated by Real-time PCR. Westernblot assay was used to compare the expression difference of c-MET and p-MET. HGF level in culture medium is determined by ELISA.
SIM-89 can inhibit 3 kinases including c-Met（IC50=297nM）, AMPK, TRKA (IC50=150.2nM). SIM-89 has an ATP competive inhibition on c-Met. By Real-time PCR, SIM-89 has been found to inhibit STAT1, JAK1, c-Met gene expression in H460 cell. P-Met expression of A549, H441, H1299 and B16F10 cell can be inhibited by SIM-89. HGF level of supernatant in culture is significantly lower than control group. Vitality of NSCLC cell lines is inhibited dependent on time and concentration by SIM-89. Induced by HGF, migration of H460, H1299 cell is inhibited.
SIM-89 has significant inhibitive effect on c-Met, TRKA kinases. It also can inhibit proliferation, migration and HGF autocrine of NSCLC cell significantly. Further study in vivo should be carried to explore the pharmacokinetics of SIM-89.