Abstract
Abstract In lung adenocarcinomas, targeted therapy with the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib is associated with longer progression free survival (PFS). However, despite the initial success, all patients progress with a median PFS of 12 to 16 months. Acquired resistance is driven by the occurrence of a secondary EGFR mutation (T790M) in about 50% of the cases and by c-Met amplification in 5 to 10 % of the cases. We report the activity of a new reversible and ATP-competitive c-Met inhibitor, EMD1214063, in the setting of primary lung adenocarcinomas harboring EGFR activating mutations and in two models of acquired resistance. EMD1214063 showed to be specifically active in c-Met amplified and c-Met dependent cells in a large panel of genotypically characterized lung cancer cell lines. In the context of acquired resistance, we studied the effect of EMD1214063 alone and in combination of afatinib, an irreversible EGFR TKI, in PC9 cells (EGFR Exon19del), H1975 cells (EGFR L858R and T790M), HCC827 (EGFR Exon19del, not c-Met amplified) and in HCC827GR cells (EGFR Exon19del and c-Met amplified). Treatment of HCC827GR cells with EMD1214063 resulted in substantial growth inhibition and induced apoptosis. The in vitro results showed a significant synergistic effect of the combination of EMD121039 and afatinib in the induction of growth inhibition in the context of c-Met amplification and EGFR T790M mutation. Combination treatment robustly suppressed expression of downstream pErk and pAkt, showing efficient suppression of PI3K and MAPK signaling. To determine whether the antitumor activity of the combination observed in vitro might also be apparent in vivo, we injected these cells in nude mice to elicit the formation of solid tumors. Mice were treated with EMD121043 (25mg/kg), afatinib (10mg/kg) or the combination of both. In H1975 xenografts only the combination therapy could significantly reduce tumor growth, thus confirming the results obtained in vitro. In the c-Met amplified setting, we treated mice harboring HCC827, HCC827GR and mixed xenografts. HCC827-driven tumors strongly responded to both afatinib monotherapy and to the combination, leading to complete remission within 40 days of therapy. HCC827/HCC827GR mixed xenografts containing 0.1%, 1% and 10% of HCC827GR cells partially responded to afatinib monotherapy; however, growth was completely abolished by combination therapy. Treatment with EMD1214063 led to significant growth reduction in mice harboring HCC827GR tumors. In this model, only the combination therapy led to massive tumor shrinkage. Assessment of cell proliferation in vivo by [18F]FLT-PET showed a decline in FLT-uptake of 40% in both the combination therapy and the EMD1214063 monotherapy. In conclusion, the combination of EMD1214063 and afatinib promote tumor regression in erlotinib acquired resistant lung cancers driven by EGFR L858R/T790M or EGFR Exon19 del/c-Met amplification. Citation Format: Sandra Ortiz-Cuarán, Jakob Schöttle, Ilona Dahmen, Martin Peifer, Caroline Wieczoreck, Mirjam Koker, Michaela A. Ihle, Alexandra Florin, Berit Pinther, Lukas C. Heukamp, Roland T. Ullrich, Roman K. Thomas. Attacking EGFR mutant lung cancer by combined EGFR and c-Met inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1690. doi:10.1158/1538-7445.AM2014-1690
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