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Poster Display session (Friday) (ID 65)
- Event: ELCC 2018
- Type: Poster Display session
- Presentations: 1
- Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
65P - Fatty acid synthase (FASN) inhibition effect on EGFR TKIs sensitive and resistant cells (ID 574)
12:30 - 13:00 | Author(s): T. Puig
EGFR tyrosine kinases inhibitors (TKIs) are effective therapies for NSCLC patients whose tumors harbor an EGFR activating mutation, however, this treatment is not curative because of both primary and secondary resistance to EGFR TKIs. Several resistance mechanisms to EGFR-TKIs have been described, among which, there is the T790M mutation. A recently described mechanism of multidrug resistance is the FASN overexpression. FASN is a multifunctional enzyme essential for the endogenous synthesis of long-chain fatty acids.
We have worked with the lung adenocarcinoma cell line PC9 carrying the EGFR TKI sensitizing exon 19 deletion (ΔE746-A750) and 3 gefitinib-resistant PC9 derived cell lines (2 T790M positive and 1 T790M negative). Cell viability was determined by the MTT method for Gefitinib, osimertinib and two FASN inhibitors (EGCG and G28). Apoptosis was assessed by PARP cleavage. Molecular effects were analyzed by studying changes in the expression and/or activation of EGFR signaling pathways by western blot. The effects of the double combination of EGFR TKIs and FASN inhibitors in all cell lines were studied and synergy between drugs was determined using CompuSyn software.
All cell lines have significantly different IC50 values for Gefitinib except for the two T790M positive ones. Osimertinib has a concentration-dependent cytostatic effect on sensitive cells. All the studied cell lines are sensitive to FASN inhibition. The cytotoxicity caused by FASN inhibition is independent of the T790M mutation that leads to gefitinib resistance. Apoptosis is induced in all cell lines at all treatments. While gefitinib and osimertinib activate the Signal Transducer and Activator of Transcription 3 (STAT3) in all cell lines, EGCG and G28 reduce the STAT3 activation found in all gefitinib-resistant cell lines. Combination experiments using FASN inhibitor G28 and EGFR TKIs show mostly additive effect and synergism at some concentrations.
In summary, we show cytotoxicity effect of EGCG and G28 in NSCLC cells sensitive and resistant to EGFR TKIs probably due to inhibition of FASN/STAT3 signalling. FASN inhibition should overcome EGFR TKI resistance and may serve as a novel target therapy to improve EGFR-based cancer therapy in lung cancer.
Clinical trial identification:
Legal entity responsible for the study:
University of Girona
All authors have declared no conflicts of interest.
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