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B.A. Helfrich
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-084 - Rational Combinations to Improve Outcome for EGFR-TKIs in NSCLCs with EGFR Mutations (ID 6002)
14:30 - 14:30 | Author(s): B.A. Helfrich
- Abstract
Background:
Background: EGFR-TKIs produce high response rates in tumors with EGFR activating mutations as first line therapy and after development of T790M resistance. But complete responses are rare and all patients progress. We conducted serial RNAseq analyses of EGFR mutant cell lines exposed to gefitinib and osimertib. We found a rapid induction of gene reprogramming indicative of WNT signaling and EMT signaling that developed within 72 hours of drug exposure and lasted through at least 57 days. Important genes involved included E-cadherin, vimentin, ZEB1&2, axin2, IL8 and others. We therefore elected to determine if inhibitors of Wnt or EMT reprograming would produce synergistic growth inhibition in EGFR mutant cell lines exposed to osimertib. Prior clinical studies indicated that the HDAC inhibitors can safely be combined with EGFR-TKIs.
Methods:
Methods: Growth inhibition in the HCC4006 line by osimertib (10-100nM) in combination with the WNT/Bcatenin inhibitors AZD1366, ICG01, E7449 (30-270nM), WntC59, IWP2-V2, LGK974 (90-810nM), and with the HDAC inhibitors etinostat (300-1000nM), panobinostat (10-50nM) and romidepsin (1-6nM) was assessed by 5 day MTT assays. Growth inhibition by osimertib (2.5-20nM) + etinostat (60-300nM) was also evaluated in the PC9, HCC827, H3255 and PC9T790M EGFR mutant lines. Analysis of the combined drug effects was by the median-drug effect method using the CalcuSyn program to determine the combination indices (CI). CI values of < 1 are indicative of drug synergy.
Results:
Results: The CI values from combining 30nM osimertib with the midrange concentration of the WNT pathway inhibitors and HDAC inhibitors in the HCC4006 line varied from 0.18 to 1.2 and most were ≤ 0.75. The tankyrase inhibitor AZD1366 produced the most synergistic effect with CI = 0.18. CI values of ≤ 0.5 were observed with WntC59 and ICG01. The HDAC inhibitors all produced CI values of ≤ 0.75 with the lowest value of 0.23 for etinostat. CI values of osimertib combined with panobinostat and romdidepsin were 0.51 and 0.73 respectively. CI values for 30 nM osimertib combined with etinostat in the other EGFR mutant cell lines were also synergistic ranging from 0.37 in PC9 to 0.96 in the H3255 line. Synergy was also observed with romidepsin and panobinostat in these lines.
Conclusion:
Conclusions: The combination of WNT pathway inhibitors or HDAC inhibitors with EGFR-TKIs produce synergistic growth inhibition and may prevent EMT and survival pathways in EGFR mutant lung cancers.
