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S. Dupasquier
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P1.07 - Poster Session/ Small Cell Lung Cancer (ID 221)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.07-002 - FAK Inhibition by PF228 Has Anti-Tumoral Effects Associated with Inhibition of Histone 3 and Aurora Kinases A/B Phosphorylation in SCLC (ID 2844)
09:30 - 09:30 | Author(s): S. Dupasquier
- Abstract
Background:
Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide. Small cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is the most aggressive histologic type, with a five-year overall survival as low as 5%. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase, which regulates integrin and growth factor signaling pathways involved in cell proliferation, survival, migration, and invasion. FAK is overexpressed and/or activated in many cancers,including SCLC. We hypothesized that FAK may represent a good target for therapeutic intervention in SCLC and tested the changes of cell phenotype and signaling events following FAK inhibition, by using PF-573,228 (PF-228) in SCLC cell lines.
Methods:
Two SCLC cell lines growing in suspension (NCI-H82 and NCI-H146), an adherent SCLC cell line (NCI-H196), and a mixed morphology SCLC cell line (NCI-H446) were treated with increasing concentrations of PF-228. Cell proliferation was evaluated by WST-1 assay, cell cycle by flow cytometry following propidium iodide (PI) and bromodeoxyuridine (BrdU) staining, and apoptosis by flow cytometry after intracellular caspase 3 staining. FAK expression/activity and signaling events downstream of FAK were evaluated by Western blotting (WB).
Results:
While PF-228 did not modify total FAK expression, it decreased the phosphorylation of FAK (Tyr 397) in a dose dependent manner in all tested SCLC cell lines. Inhibition of FAK activity by PF-228 significantly decreased cell proliferation, induced cell cycle arrest in G2/M phases,decrease DNA replication and increased apoptosis in all tested cell lines proportionally to the dose. Regarding signaling events, we observed that inhibition of FAK activity induced the inhibition of phosphorylation of histone-3 (Ser 10) and Aurora Kinase A (Thr288) and B (Thr232). Figure 1
Conclusion:
These results show that FAK activity is required for proliferation, cell cycle progression, and survival in SCLC cell lines, suggesting that this pathway is central to SCLC biology. The antitumoral effects of PF-228 may occur through (1) the inhibition of histone-3 phosphorylation mediated by the inhibition of Aurora kinase B and leading to cell cycle arrest in G2/M phase and (2) the inhibition of Aurora kinase A leading to decreased DNA replication.
