Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway

Abstract

The genetic concept of synthetic lethality provides a framework for identifying genotype-selective anticancer agents. In this approach, changes in cellular physiology that arise as a consequence of oncogene activation or tumor suppressor gene loss, rather than oncoproteins themselves, are targeted to achieve tumor selectivity. Here we show that agonists of the TRAIL death receptor DR5 potently induce apoptosis in human cells overexpressing the MYC oncogene, both in vitro and as tumor xenografts in vivo. MYC sensitizes cells to DR5 in a p53-independent manner by upregulating DR5 cell surface levels and stimulating autocatalytic processing of procaspase-8. These results identify a novel mechanism by which MYC sensitizes cells to apoptosis and validate DR5 agonists as potential MYC-selective cancer therapeutics.

The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

“…Increases in endogenous or ectopic c-Myc expression can either enhance (Ruggero et al, 2004;Wang et al, 2004b) or inhibit apoptosis (Bellas and Sonenshein, 1999;Ryu et al, 2003), depending on the cell type studied. In primary mammary tumors and in Hs578T cells, c-Myc tends to induce apoptosis (Chen et al, 1998;Liao and Dickson, 2003).…”

Overview of cell death signaling pathways

“…151 Myc also has been shown to upregulate expression of TRAIL receptors in some tumor cells. 167 c-Myc enhances the apoptotic activity of death receptor signaling proteins by engaging the mitochondrial apoptotic pathway. 168 Thus, myc may serve as a indicator of potential TRAIL sensitive tumor cells in clinical trials.…”

Mechanisms of resistance to TRAIL-induced apoptosis in cancer

“…91 Furthermore, when DR5 is upregulated by either MYC oncogene or doxorubicin, the normal cells can become sensitive to either the DR5 receptor agonistic antibodies or TRAIL. 24,92 In most of the normal cells tested, DR4 shows much lower expression than that of DR5, which may also reduce TRAIL sensitivity. 91 In general, current data suggest that, in certain normal cells or tissues, the ratio of expression between real death receptor DR4 and DR5, and decoy receptors DcR1 and DcR2, may determine the TRAIL sensitivity.…”