Abstract 834: The microtubule-disrupting drug BNC105 is a potent inducer of acute apoptosis in CLL

Abstract

Abstract The cytotoxicity of microtubule-disrupting drugs such as the vinca alkaloids has generally been considered to occur during mitosis. However, we have reported that vinca alkaloids can induce apoptosis rapidly (<6 h) from all phases of the cell cycle, and even in post-mitotic quiescent cells such as peripheral chronic lymphocytic leukemia (CLL). Microtubule disruption still appears to be required as acute apoptosis also occurs with combretastatin A4 (CA4) which targets the colchicine-binding site on tubulin, but not with paclitaxel which stabilizes microtubules. The mechanism of this rapid apoptosis is associated with two different pathways: induction of the pro-apoptotic BCL2 family member NOXA and activation of c-Jun N-terminal kinase (JNK). A proof-of-concept clinical trial revealed that vincristine activated JNK in peripheral lymphocytes of patients with CLL, but failed to induce NOXA or apoptosis, suggesting that this might not be the best microtubule disruptor to use clinically. Further investigation revealed that the vascular disrupting agent BNC105 (provided by Bionomics Ltd), which also targets the colchicine-binding site on tubulin, is a much more potent activator of JNK and inducer of NOXA in various leukemia cell lines and freshly isolated CLL cells. BNC105 induced ATF3, phospho-ATF2 and NOXA proteins and activated JNK at low nM concentrations. As a single agent, BNC105 induced JNK-dependent apoptosis in CLL cells ex vivo at clinically achievable concentrations, and much more potently than either vinblastine or CA4. The combination of BNC105 with the BCL2 inhibitor ABT-199 increased apoptosis levels in CLL cells and various leukemia cell lines. Furthermore, the addition of BNC105 partially overcame stroma-mediated resistance to ABT-199 in CLL cells suggesting potential efficacy of this combination in the lymph node microenvironment. Survival of normal lymphocytes was not affected by BNC alone or in combination, even though JNK was activated. These results suggest BNC105 is an excellent candidate for clinical trials to induce acute apoptosis in hematopoietic malignancies. Citation Format: Darcy J.P. Bates, Edmundo J. Feris, Alexey V. Danilov, Alan Eastman. The microtubule-disrupting drug BNC105 is a potent inducer of acute apoptosis in CLL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 834. doi:10.1158/1538-7445.AM2014-834