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MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
MO01.06 - Screening for drugs that overcome Gefitnib resistance in EGFR mutation-positive non-small cell lung cancer cells. (ID 2957)
10:30 - 12:00 | Author(s): Y. Xue
EGFR mutation-positive Non-Small Cell Lung Cancer (NSCLC) patients who show an initial dramatic response to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy almost always acquire resistance due to secondary resistance mutations on EGFR or other mechanisms. Strategies to overcome such acquired resistance have therefore become critical to improve TKI-based targeted therapy. One strategy is the development of therapeutic agents to be used in combination with EGFR-TKI to treat EGFR mutation-positive relapsed patients. Although several candidate drugs targeting putative resistance pathways in NSCLC cells have been attempted in combination with EGFR-TKI, a systematic screening has not been reported. We seek to screen a small molecule library for compounds that would specifically enhance the cytotoxic effect of TKIs on EGFR mutation-positive tumor cells bearing acquired resistance mutations.
We have used MTS assay to screen a library containing about 1000 FDA approved drugs, 600 bioactive compounds, and 400 natural products, to identify compounds that when used in combination with 1µM Gefitnib, can result in significantly more toxicity to Gefitnib-resistant NSCLC cell line H1975 than either Gefitnib or the compound alone. The EGFR on H1975 contains both a TKI-sensitive mutation L858R and a resistant mutation T790M.
The screening identified one candidate compound 18G06, an experimental natural product that belongs to a family of drugs currently used for heart disease. The compound has an IC50 of 270nM on H1975, and acts synergistically with Gifitnib to affect cell apoptosis, suggesting that the drug can overcome Gefitnib resistance in H1975. Test of 4 other known drugs in this family showed that they all have sub-microM IC50 values against H1975, but only Drug D had synergistic effect with Gefitnib, while other three drugs showed only additive effects. In addition, 18G06 or Drug D can overcome Gefitnib resistance of H1650 cells, a resistant NSCLC cell line with TKI-sensitive exon19 microdeletion and a TKI-resistant PTEN deletion. However, these two drugs, when used alone or with Gefitnib, had little effect on A549 cells, a resistant NSCLC line with wildtype EGFR. Biochemical evidence suggested that the improved Gefitnib sensitivities of H1975 and H1960 were correlated with specific synergistic inhibition of the ERK signaling pathway during combination treatment. Finally, combination therapy with Drug D and Gefitnib inhibited the growth of tumors formed by inoculated H1975 cells in nude mice to a greater extent than did treatment with either drug alone.
We identified two specific members of a family of therapeutics for heart disease that, when each combined with Gefitinib, have synthetic lethality effect on H1975 and H1960. The FDA-approved Drug D can be readily tested in clinical trials with Gefitnib to potentially reverse TKI-resistance of EGFR mutation-positive patients in targeted therapy.
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