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M. Kuroda
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-084 - Linker-Phosphorylated Smad2 and STAT3 Induce Resistance to Tyrosine Kinase Inhibition in Lung Cancer (ID 6092)
14:30 - 14:30 | Author(s): M. Kuroda
- Abstract
Background:
Cancer-associated inflammation develops resistance to the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) harboring oncogenic EGFR mutations. The molecular mechanisms how the cytokines produced and activated in the tumor microenvironment such as transforming growth factor-β (TGF-β) and IL-6 regulate EGFR-TKI resistance remain largely unknown.
Methods:
To determine the mechanisms how Smad-mediated TGF-β signaling and STAT3-mediated IL-6 signaling regulate sensitivity and resistance to gefitinib, we treated HCC827 adenocarcinoma cell line harboring an oncogenic deletion within the EGFR (delE746-A750) with gefitinib, an activin receptor-like kinase5 (ALK5) inhibitor, EW-7197 and/or IL-6.
Results:
IL-6 and a TGF-β antagonist, EW-7197 synergized to suppress gefitinib-induced apoptosis of HCC827. Treatment with gefitinib induced interaction between unphosphorylated Smad2 and STAT3 in cytoplasm. IL-6 and/or EW-7197 significantly upregulated phosphorylation of Smad2 linker region. Linker-phosphorylated Smad2 at serine 245 and 255 residues interacted with phosphorylated STAT3 at tyrosine 705 and serine 727 residues to suppress gefitinib-induced apoptosis of HCC827. In contrast with Smad2, IL-6 and EW-7197 synergized to downregulate the expression of Smad3.
Conclusion:
Our data suggest that inhibition of phosphorylation of Smad2 linker region and STAT3 could prevent EGFR-TKI resistance in NSCLCs.
