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Cancer Lett. 2017 Dec 28;411:19-26. doi: 10.1016/j.canlet.2017.09.040. Epub 2017 Oct 4.

HSP90 inhibitor (NVP-AUY922) enhances the anti-cancer effect of BCL-2 inhibitor (ABT-737) in small cell lung cancer expressing BCL-2.

Author information

1
Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
2
Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.
3
Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
4
Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea; Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea. Electronic address: 77kangseo@gmail.com.
5
Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea. Electronic address: leedaeho@amc.seoul.kr.

Abstract

Small cell lung cancer (SCLC) cannot be efficiently controlled using existing chemotherapy and radiotherapy approaches, indicating the need for new therapeutic strategies. Although ABT-737, a B-cell lymphoma-2 (BCL-2) inhibitor, exerts anticancer effects against BCL-2-expressing SCLC, monotherapy with ABT-737 is associated with limited clinical activity because of the development of resistance and toxicity. Here, we examined whether combination therapy with ABT-737 and heat shock protein 90 (HSP90) inhibitor NVP-AUY922 exerted synergistic anticancer effects on SCLC. We found that the combination of ABT-737 and NVP-AUY922 synergistically induced the apoptosis of BCL-2-expressing SCLC cells. NVP-AUY922 downregulated the expression of AKT and ERK, which activate MCL-1 to induce resistance against ABT-737. The synergistic effect was also partly due to blocking NF-κB activation, which induces anti-apoptosis protein expressions. However, interestingly, targeting BCL-2 and MCL-1 or BCL2 and NF-κB did not induce the cytotoxicity. In conclusion, our study showed that combination of BCL2 inhibitor with HSP90 inhibitor increased activity in in vitro and in vivo study in only BCL-2 expressing SCLC compared to either single BCL2 inhibitor or HSP inhibitor. The enhanced activity might be led by blocking several apoptotic pathways simultaneously rather than a specific pathway.

KEYWORDS:

BCL-2 inhibitor; Combination therapy; HSP90 inhibitor; Small cell lung cancer

PMID:
28987383
DOI:
10.1016/j.canlet.2017.09.040
[Indexed for MEDLINE]

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