The upregulation of anti-apoptotic BCL2 family members enhances the survival of cancer cells, such as in chronic lymphocytic leukemia (CLL). A class of inhibitors (termed BH3 mimetics) has been developed to inhibit BCL2 proteins and selectively kill cancer cells. These inhibitors function by occupying the groove through which BCL2 proteins interact with their binding partners. ABT-737 is a high affinity inhibitor of BCL2 and BCLXL, and navitoclax, which has a similar binding profile, has shown efficacy in clinical trials. However, resistance occurs when the cancer cells rely on additional BCL2 members, such as MCL1 or BFL1, which are not inhibited by ABT-737. Using leukemia cell lines, we compared several BH3 mimetics reported to inhibit multiple BCL2-family proteins (including MCL1 and BFL1), with the goal of enhancing the efficacy of ABT-737. We found that none of these compounds functioned as true BH3 mimetics. Instead, the compounds induced ER stress and upregulated the pro-apoptotic protein NOXA. Furthermore, two of these compounds, S1 and gossypol, sensitized leukemia cells to ABT-737 in a NOXA-dependent manner. NOXA induced by S1 or gossypol is dependent on increased reactive oxygen species or increased cytoplasmic calcium, respectively. We also tested these drug combinations in CLL cells ex vivo. S1 and gossypol combined with ABT-737 to selectively kill CLL cells but not normal lymphocytes. Interaction between CLL cells and stroma in patients promotes resistance to BCL2 inhibitors through the upregulation of MCL1 and BFL1. Co-incubation of CLL cells ex vivo with CD40 ligand-expressing stroma mimics the resistance to BCL2 inhibitors seen in patients. Importantly, this resistance was overcome when S1 or gossypol was combined with ABT-737. Our results show two novel mechanisms for upregulating NOXA and sensitizing leukemia cells to ABT-737. These combinations also kill CLL cells exposed to stroma, and may therefore target residual CLL cells in vivo, thus improving clinical outcome.

Citation Format: Ryan S. Soderquist, Darcy J. P. Bates, Alan Eastman. S1 and gossypol induce NOXA through increased reactive oxygen species or cytoplasmic calcium and sensitize to ABT-737. [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 4412. doi:10.1158/1538-7445.AM2013-4412

©2013 American Association for Cancer Research
2013