Abstract 3522: Vincristine activates c-Jun N-terminal kinase in chronic lymphocytic leukemia in vivo.

Abstract

Abstract Chronic lymphocytic leukemia (CLL) is a cancer of B cell lymphocytes whose survival depends on the anti-apoptotic activity of Bcl-2 family proteins. Due to the low growth fraction of CLL cells, drugs that kill during mitosis, such as the microtubule-targeting vinca alkaloids, are not expected to be effective. However, we have found that vincristine and vinblastine can act independently of mitosis and induce acute apoptosis in freshly isolated CLL cells. The mechanism of this effect still depends on destabilization of microtubules as similar events occur with combretastatin A4 which destabilizes microtubules through binding to a different site on tubulin. Vinca-mediated apoptosis in CLL cells can be enhanced by addition of the cyclin-dependent kinase (CDK) inhibitor dinaciclib, killing cells acutely within 6 h. Dinaciclib functions by inhibiting CDK9, suppressing transcription and preventing expression of Mcl-1. The combination of dinaciclib and vinca alkaloids depends on vinca-induced phosphorylation of c-Jun N-terminal kinase (JNK). Therefore, we investigated whether JNK phosphorylation occurs in peripheral blood CLL cells in patients receiving vincristine. Patients received 2 mg vincristine intravenously by infusion over 5 minutes. Venous blood samples were obtained at time zero (pre-treatment) and post drug administration for up to 6 h. Patients then continued to receive chemotherapy treatment as prescribed by their primary oncologist. Pre-treatment CLL cells were studied ex vivo for JNK phosphorylation on exposure to vincristine. These studies showed that CLL cells phosphorylated JNK in response to clinically relevant concentrations of vincristine (10-50 nM). In the CLL cells from all 4 patients studied thus far, vincristine led to rapid (≤ 1 h) JNK phosphorylation which was sustained for 4-6 h post vincristine administration. These proof-of-principle study results provide justification for the development of a Phase I study to define the effect of the combination of vinca alkaloids and dinaciclib in patients with CLL. Citation Format: Darcy JP Bates, Alexey V. Danilov, Bernard B. Beaulieu, Lionel D. Lewis, Alan Eastman. Vincristine activates c-Jun N-terminal kinase in chronic lymphocytic leukemia in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3522. doi:10.1158/1538-7445.AM2013-3522