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H. Zhang
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-049 - Efficacy of Focal Adhesion Kinase (FAK) Inhibition in RAS Mutant and EGFR Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 728)
09:30 - 09:30 | Author(s): H. Zhang
- Abstract
Background:
Focal Adhesion Kinase (FAK) is overexpressed in many types of tumors, including lung cancer. We sought to determine the antitumor activity of various FAK inhibitors in NSCLC cell lines with RAS mutations as well as in epidermal growth factor receptor (EGFR) mutant cell lines with known resistance to EGFR tyrosine kinase inhibitors (TKIs).
Methods:
The effects of FAK inhibitors (NVP-TAE226, PF-562271, PF-573228, Y15) were tested against a variety of lung cancer cell lines (H157, H358, H460, H727, H1299, A549, H1650, H1975). Cell viability and clonogenic assays were performed to determine the IC50 of each agent. Western blot analysis was performed to determine alterations in relevant signaling proteins. RNA interference studies were done to elucidate mechanisms of action. Xenograft experiments were conducted to evaluate the efficacy of Y15 in vivo.
Results:
Y15 is more potent compared to the most selective FAK inhibitor PF-574228, with comparable to slightly more potent activity compared to PF-573228 and TAE-226 (Table 1). Y15 blocked autophosphorylation of FAK in a time- and dose-dependent manner. It caused dose-dependent decrease of lung cancer cell viability and clonogenicity. Apoptosis through Bcl-2 and Bcl-xL downregulation induced by Y15 occurs in an Akt-independent manner via JNK activation. Moreover, knockdown of Bcl-2 or Bcl-xL potentiated the effects of Y15. The combination of various inhibitors of the Bcl-2 family of proteins with FAK inhibitors demonstrated synergy in multiple lung cancer cell lines in vitro. Y15 blocked tumor growth of RAS mutant (A549 with KRAS mutation and H1299 with NRAS mutation) as well as EGFR mutant cell lines with known resistance to EGFR TKIs (H1650 and H1975) in xenograft experiments.Table 1. The IC50 values of FAK inhibitors in lung cancer cell lines as determined by MTS assay.
H157 H358 H460 H727 H1299 A549 H1650 H1975 TAE226 IC50 (uM) 7.46 3.18 4.32 0.30 2.98 2.59 2.30 2.88 PF-562271 IC50 (uM) 5.76 6.38 4,26 2.26 3.94 5.41 5.31 5.47 PF-573228 IC50 (uM) 11.39 27.49 6.17 2.80 9.18 9.08 20.70 13.20 Y15 IC50 (uM) 2.1 2.72 3.16 1.30 3.88 3.49 1.9 1.56
Conclusion:
FAK inhibition using Y15 demonstrated efficacy both in vitro and in vivo in lung cancers with either oncogenic RAS or EGFR mutations. The combination of FAK inhibitors with inhibitors of the Bcl-2-family of anti-apoptotic proteins has synergistic activity in these RAS and EGFR mutant NSCLC cell line models.
