Abstract C129: TAS-116, an orally available HSP90α and β selective inhibitor, exhibits synergistic effects in combination with taxanes in EGFR-tyrosine kinase inhibitor-resistant human NSCLC xenograft models through the downregulation of key molecules involved in drug resistance of cancer chemotherapy.

Abstract

Abstract Background: In advanced NSCLC, EGFR-tyrosine kinase inhibitors (EGFR-TKI) have shown limited effect on lung squamous cell carcinoma (LSCC) or NSCLC harboring either a mutation in the K-RAS oncogene or lacking an activated mutation in EGFR. Though several cytotoxic drugs have been used in these EGFR-TKI-resistant settings, clinical outcomes have been generally poor. It has been shown that several antiapoptotic molecules regulated by PI3K/AKT and MAPK signaling, are involved in drug resistance to cancer chemotherapy. One of the possible approaches to overcome such drug resistance is via simultaneous inhibition of multiple signaling pathways. We have previously reported on an orally available highly selective HSP90α and β inhibitor, TAS-116. Because TAS-116 leads to downregulation of multiple molecules involved in various signaling pathways through HSP90 inhibition, we investigated the potential utility of TAS-116 on LSCC and K-RAS mutated NSCLC in combination with taxanes. Materials and Methods: In vitro drug combination effects were evaluated with calculation of combination index. The amount and the phosphorylation status of cellular proteins were determined by western blot with appropriate antibodies. Antitumor activities of TAS-116 alone and in combination with taxanes were evaluated in human NSCLC xenograft models. The inhibition and induction study of cytochrome P450 (CYP) by TAS-116 were evaluated using human liver microsomes and human cryopreserved hepatocytes, respectively. Results: TAS-116 showed synergistic effects in combination with docetaxel (DTX) and paclitaxel (PTX) against LSCC cell lines. TAS-116 enhanced taxane-mediated apoptosis. To clarify the mode of action in these combinations, we measured the amount and the phosphorylation status of apoptosis-related proteins. TAS-116 decreased phosphorylation of BAD and YBX1, through the downregulation of upstream kinases, AKT and RAF1. TAS-116 synergistically inhibited tumor growth in both human LSCC and K-RAS mutated NSCLC xenograft models in combination with PTX or DTX. With regard to drug-drug interaction potential at effective concentrations, TAS-116 did not inhibit or induce CYP3A4 which is important in taxane metabolism. Conclusion: TAS-116 in combination with taxanes enhanced apoptosis induction and exhibited synergistic antitumor activity against LSCC and K-RAS mutated NSCLC xenograft models through downregulation of key factors involved in drug resistance in cancer chemotherapy. The combination of TAS-116 and taxanes could be a promising approach to treat EGFR-TKI-resistant NSCLC including LSCC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C129. Citation Format: Hiromi Muraoka, Akira Kanoh, Akihiro Hashimoto, Kenjiro Ito, Takamasa Suzuki, Kouichi Takahashi, Chihoko Yoshimura, Makoto Kitade, Kazuhiko Yonekura, Shuichi Ohkubo, Teruhiro Utsugi. TAS-116, an orally available HSP90α and β selective inhibitor, exhibits synergistic effects in combination with taxanes in EGFR-tyrosine kinase inhibitor-resistant human NSCLC xenograft models through the downregulation of key molecules involved in drug resistance of cancer chemotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C129.