Abstract 5477: Multiple BH3 mimetics antagonize anti-apoptotic MCL1 by inducing the endoplasmic reticulum stress response and upregulating the BH3-only protein NOXA

Abstract

Abstract Many small molecules have been designed or discovered that mimic the binding of BH3-only proteins to the hydrophobic groove of anti-apoptotic BCL2 proteins and thus have potential as anticancer agents. For example, ABT-737 preferentially binds and inhibits BCL2 and BCL-XL but not MCL1. It is generally believed that specific inhibitors of anti-apoptotic BCL2 proteins should induce apoptosis in a BAX/BAK-dependent manner. While this is true for ABT-737, many other purported BH3 mimetics have been shown to kill cells in a BAX/BAK-independent manner leading to the conclusion that they function through alternative undefined targets. The selectivity of these BH3 mimetics for BCL2, BCL-XL, or MCL1 has been established in vitro; whether they inhibit these proteins in cells has not been rigorously investigated. In this study, we used a panel of leukemia cell lines to assess the ability of seven putative BH3 mimetics to affect the interaction of BCL2 family members in a cell-based system. We show that ABT-737 is the only BH3 mimetic that inhibits BCL2 in cells as assessed by displacement of BAD from BCL2. The other six BH3 mimetics activated the endoplasmic reticulum (ER) stress response and induced ATF3 resulting in induction of NOXA which binds to and inhibits the anti-apoptotic MCL1 protein. The fact that 6 different compounds, all of which are thought to be BH3 mimetics, can induce ER stress suggests that they may interact with a common target although whether this is a BCL2 family member remains to be established. In most cancer cells, inhibition of either BCL2/X or MCL1 does not acutely induce apoptosis. However, by combining two BH3 mimetics, one that inhibits BCL2 and one that induces NOXA, apoptosis is induced within 6 h in a BAX/BAK-dependent manner. As MCL1 is a major mechanism of resistance to ABT-737, these results suggest a novel strategy to overcome this resistance. In summary, these results identify a novel signaling pathway through which many BH3-mimetics inhibit MCL1 and suggest the potential use of these agents as adjuvants in combination with various chemotherapy strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5477. doi:10.1158/1538-7445.AM2011-5477