142 TAS-2913 is a Mutant Selective EGFR Inhibitor for NSCLC: Characterization Against EGFR T790M in Cell and Xenograft Models

Abstract

activation of ErbB3 and to sensitize platinum-resistant cells to subsequent chemotherapy. Materials and Methods: Cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian cancer cell lines were acquired from ATCC. Primary ascites cells were isolated from advanced stage ovarian cancer patients who had undergone prior therapy. Cells were propagated in vitro and cell viability assays were performed in the presence of platinum-based drugs, taxanes, or MM-121. Heregulin stimulation and inhibition of signaling by MM-121 were evaluated by quantitative western blotting and reverse phase protein arrays. Drug sensitivity and signaling were assessed for A2780 and A2780cis using subcutaneous xenografts. Basal heregulin levels were measured by ELISA and mRNA-based methods. Results: Consistent with our hypothesis that platinum resistance can be mediated by ligand-driven ErbB3 signaling, basal heregulin levels were increased in A2780cis cells relative to A2780 cells, and growth of A2780cis (but not A2780) xenografts was sensitive to MM-121. Interestingly, patientderived ascites cells exhibited differential sensitivity to paclitaxel and platinum-based drugs, and cells collected serially from the same patient over the course of treatment provided evidence of acquired resistance. Ascites cells responded differently to heregulin stimulation and inhibition by MM-121, suggesting that only a subset of cells develop resistance through this mechanism. In most cases, cells that are responsive to heregulin are also responsive to MM-121, and MM-121 sensitizes some of these cells to paclitaxel treatment. Conclusion: Platinum resistance is associated with increased heregulin expression or responsiveness to heregulin in cell lines and primary ascites cells. MM-121 could potentially play a role in overcoming platinum resistance or in sensitizing cells to subsequent chemotherapy. As only a subset of cells use this mechanism, a biomarker-based strategy to identify patients could be useful. A Phase 2 randomized open label study of MM-121 in combination with paclitaxel versus paclitaxel alone is currently enrolling patients with advanced ovarian cancer.