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H. Lee
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-004 - Paxillin Confers Resistance to TKI via Modulating BIM and Mcl-1 Protein Stability (ID 152)
09:30 - 09:30 | Author(s): H. Lee
- Abstract
Background:
Tyrosine kinase inhibitors (TKIs) have been documented to have substantial clinical benefits to non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. TKI resistance occurs in nearly all patients who receive TKI targeting therapy, resulting in a modest overall survival benefit. Therefore, establishing a biomarker for early prediction and exploring the mechanism of primary TKI resistance is essential for improving the therapeutic efficacy in NSCLC patients.
Methods:
In this study, we provide evidence indicating that paxillin (PXN) overexpression may confer gefitinib resistance in EGFR-mutant lung cancer cells.
Results:
Mechanistically, PXN-mediated ERK activation is responsible for gefitinib resistance via decreased BIM and increased Mcl-1 expression due to modulating their protein stabilities by phosphorylation of BIM at Serine 69 and Mcl-1 at Threonine 163. The mechanistic action in the cell model was further confirmed by the observation of xenograft tumors in nude mice, revealing that the PXN-mediated gefitinib resistance was conquered by ERK inhibitor (AZD6244) and Bcl-2 family inhibitor (obatoclax), but the gefitinib resistance overcome by AZD6244 is more effective than that of obatoclax.
Conclusion:
Therefore, we suggest that PXN expression may be useful in predicting primary TKI resistance, and combining TKI with ERK inhibitors may clinically benefit EGFR-mutant NSCLC patients whose tumors exhibit high PXN expression.
