Abstract B188: Preclinical antitumor activity of ASP8273, a mutant-selective irreversible EGFR inhibitor in an AXL-overexpressing NSCLC model

Abstract

Abstract Background: Activating mutations of epidermal growth factor receptor (EGFR) are associated with the high sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, acquired resistance limits the clinical efficacy of EGFR-TKIs. Several mechanisms of the acquired resistance have been described, including gatekeeper T790M mutation and MET amplification. Overexpression of AXL, a receptor type tyrosine kinase and/or its ligand, GAS-6 have been identified in a subset of NSCLC patients with acquired resistance, and inhibition of AXL has been shown to restore sensitivity to erlotinib in nonclinical resistant models, suggesting that AXL is also involved in EGFR-TKI resistance of NSCLC. ASP8273 is a mutant-selective irreversible EGFR inhibitor currently in clinical trials (ClinicalTrials.gov Identifier: NCT02113813, NCT02192697, NCT02500927). We have previously reported that ASP8273 selectively inhibited kinase activities of EGFR activating and T790M mutations compared to wild type EGFR, and induced tumor regression in HCC827 and NCI-H1975 xenografted mice. In this study, we evaluated the antitumor activity of ASP8273 against AXL overexpressing PC-9 cells. Method: PC-9 vec. cells and PC-9 AXL cells were constructed by the infection of pMXs-puro vector and AXL coding vector, respectively into PC-9, a NSCLC cell line with EGFR exon 19 del activating mutation. Inhibitory effects of ASP8273 and other EGFR-TKIs, including erlotinib on EGFR and AXL signaling and cell proliferation were investigated in PC-9 vec. and PC-9 AXL cells. In vivo antitumor effect was also examined in subcutaneously implanted with PC-9 AXL. Result: ASP8273 at 1 μmol/L inhibited cell growth associated with the inhibition of EGFR, AXL, AKT, and ERK phosphorylation in PC-9 AXL. On the other hand, EGFR-TKIs at 1 μmol/L did not show cell growth inhibition in PC-9 AXL cells, whereas those showed cell growth inhibition in PC-9 vec. cells. EGFR-TKIs inhibited the phosphorylation of EGFR but not AXL, AKT, and ERK in PC-9 AXL cells. In an in vivo xenograft model using PC-9 AXL, once-daily oral administration of ASP8273 at 50 mg/kg induced statistically significant tumor growth inhibition although the other EGFR-TKIs did not. Conclusion: These results suggest that overexpression of AXL confers resistance to EGFR-TKIs in NSCLC cells and ASP8273 may show antitumor activity against EGFR-TKIs-resistant NSCLC patients with AXL expression. Citation Format: Naoki Kaneko, Hiroaki Tanaka, Satoshi Konagai, Hiroko Yamamoto, Hideki Sakagami, Tomohiro Eguchi, Takahiro Matsuya, Masamichi Mori, Hiroyuki Koshio, Tadashi Terasaka, Masaaki Hirano, Sadao Kuromitsu, Masahiro Takeuchi. Preclinical antitumor activity of ASP8273, a mutant-selective irreversible EGFR inhibitor in an AXL-overexpressing NSCLC model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B188.