Abstract 2022: Hsp90 inhibitor (NVP-AUY922) enhances anti-cancer effect of Bcl-2 inhibitor (ABT-737) in small cell lung cancer
Authors: Yang Hannah , Park Kang-Seo , Choi Junyoung , Kim Sang-We Kim , Lee Dae Ho 
Published: July 2017

Background: Bcl-2 family is a group of apoptosis regulators that plays an anti-apoptotic role for cell survival and is known to contribute to induce chemotherapy resistance in small cell lung cancer (SCLC). ABT-737 is an anti-cancer drug that induces apoptosis by selectively blocking the activities of Bcl-2 and Bcl-xL, but not Mcl-1. Consequently, the efficacy of ABT-737 is largely restricted in the presence of Mcl-1. Heat-shock-protein 90 (Hsp90) is highly expressed in most tumors and Hsp90 inhibitors induce the proteasomal degradation of Hsp90 client proteins. In addition, Hsp90 inhibitor can reduce Mcl-1 expression, a down-stream of Akt and Erk pathway. Furthermore, Hsp90 inhibitor inhibits activities of NF-κB by degradation of IKK. Thus, we show that downregulation of Mcl-1 and NF-κB by Hsp90 inhibitor can lead to synergistic pro-apoptotic effects with ABT-737.

Materials and methods: The proliferative activity, apoptotic activities, and expression of apoptotic proteins were assessed in SCLC cell lines after treatment with ABT-737, NVP-AUY922, or both drugs. The synergy effects of ABT-737 and NVP-AUY922 were analyzed by cell viabilities with different concentrations in SCLC cell lines, and the combination index values were &lt; 1. In addition, the synergy effects of the drugs were showed with xenograft model with human SLCL cell line in vivo.

Results: Here, we show that NVP-AUY922, an Hsp90 inhibitor, can potentiate the pro-apoptotic effects of ABT-737 not only by reducing the levels of Akt but also by inhibiting pNF-κB, both of which are proteins regulating apoptosis signaling. Western blot analysis revealed that proteins associated with apoptosis such as PARP, Caspase 3 and 7 were more upregulated in SCLC cells exposed to the drug combination than in cells exposed to NVP-AUY922 or ABT-737 alone. In addition, Annexin V & dead cell assay showed dual inhibition of the Hsp90 and Bcl-2 signaling pathways more increased apoptotic cells and dead cells in SCLC. In our result, ABT-737 induced apoptosis by blocking Bcl-2 activation, and NVP-AUY922 blocked the levels of Hsp90 client proteins, Akt and pErk, ultimately leading to decreased level of Mcl-1. In addition, NVP-AUY922 induced degradation of IKK, and increased IκB-α inhibited activation of NF-κB. And this combination treatment showed higher BIM and BID expression, pro-apoptotic proteins, than single treatment. Furthermore, synergy effects of combination were verified in xenograft model with human SCLC cell line.

Conclusions: Consequently, NVP-AUY922 synergizes with ABT-737 to induce apoptosis by reducing activities of Mcl-1 and NF-κB in SCLC. This study suggests that adopting an appropriate combination of drugs can lead to better outcomes compared with monotherapy in SCLC.

Citation Format: Hannah Yang, Kang-Seo Park, Junyoung Choi, Sang-We Kim Kim, Dae Ho Lee. Hsp90 inhibitor (NVP-AUY922) enhances anti-cancer effect of Bcl-2 inhibitor (ABT-737) in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2022. doi:10.1158/1538-7445.AM2017-2022