Abstract 3922: Ganetespib demonstrates strong anti-tumor effect in acquired EGFR-TKI resistance NSCLC cells

Abstract

Abstract Purpose: Epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKIs) are the standard first-line treatment of advanced non-small cell lung cancer (NCSLC). However, almost all patients eventually acquire resistance to EGFR-TKIs, and novel therapeutic strategies to overcome the acquired resistance have been required. Heat-shock protein 90 (Hsp90) is a chaperon protein involved in folding and stabilization of client proteins essential for cancer cell growth and survival. Ganetespib (STA-9090) is one of the second-generation Hsp90 inhibitors with strong anti-tumor effect on NSCLC cells. In this study, we evaluated the anti-tumor effect of ganetespib in EGFR-TKI sensitive and acquired resistance NSCLC cell lines. Materials and Methods: We treated 4 EGFR-mutant NSCLC cell lines (HCC827, HCC4006, PC-9 and HCC4011), and 14 experimentally established EGFR-TKIs (gefitinib or afatinib) resistance cell lines with ganetespib. The EGFR-TKI resistance mechanism consisted of EGFR T790M second mutation, MET amplification, epithelial-to-mesenchymal transition (EMT) and cancer stem cell-like features. We determined cell proliferation by MTS assay and calculated the IC50 values. We also performed Western blotting to investigate downstream signaling pathways. Results: The IC50 values in parental NSCLC cell lines ranged from 1.3nM to 15nM, and those in acquired EGFR-TKI resistant cell lines ranged from 0.87nM to 25nM, which suggests strong anti-tumor effect of ganetespib. In addition, this effect was observed regardless of the resistant mechanisms, including EMT. Ganetespib suppressed EGFR activation in EGFR-TKI resistance cells harboring EGFR T790M second mutation. Also, ganetespib suppressed MET activation in EGFR-TKI resistance cells harboring MET amplification. Conclusion: Ganetespib showed strong anti-tumor effect in acquired EGFR-TKI resistance NSCLC cells regardless of the resistant mechanisms, suggesting that ganetespib could be a promising therapeutic option in the treatment of NSCLC with acquired EGFR-TKI resistance. Citation Format: Eisuke Kurihara, Kazuhiko Shien, Hidejiro Torigoe, Yuta Takahashi, Yusuke Ogoshi, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka. Ganetespib demonstrates strong anti-tumor effect in acquired EGFR-TKI resistance NSCLC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3922.