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several key pieces of information have been accumulated over the past years concerning both activation and regulation of the non-canonical nf-kb pathway in cancer. a central role in the activation and regulation of this pathway is played by the e3 ubiquitin ligases cellular flice inhibitory protein (cflip), which contains an n-terminal homologous to death domains (dd) and two b-cell lymphoma-2 (bcl-2) homology domains. in response to tumor necrosis factor (tnf) or other pro-apoptotic stimuli, cflip is activated by the iaps (inhibitor of apoptosis proteins)-mediated ubiquitination, leading to its oligomerization and subsequent translocation to plasma membrane. while the expression of cflip short form (cflips) is generally induced in cancer cells, the majority of them lacks bcl-2 homology domains and their activity is constantly repressed by the ubiquitination and degradation of the long form of cflip (cflipl). in cancer, the expression of the long form of cflipl has been inversely correlated to patient prognosis, suggesting that higher levels of cflipl may be therapeutically beneficial in the treatment of hematological malignancies ⁴⁸ , while it is still a controversial issue in solid tumors, especially colon carcinomas, where high expression of cflip is an adverse prognostic factor. this is one of the most prominent areas of intensive research and several key pieces of information have been accumulated over the years.

as a next step, we developed a mathematical model of the intrinsic apoptotic switch that could predict the response of individual breast cancer cell lines to smac-mimetic compounds. this model faithfully recapitulated experimental observations of the bistable switch in breast cancer cells. we then used the model to predict the response of breast cancer cell lines to compound a (cpa), which is a pan-iap bivalent smac mimetic. compound a has been shown to bind to both iap1 and iap2 in the tnf-signaling pathway and to induce autocrine tnf secretion [ 23 ]. we assessed the response of diverse breast cancer cell lines to iap inhibition using the computational model and a subset of these cell lines were subsequently tested in a mouse xenograft model. here, we show that the computational model can predict the response of breast cancer cell lines to compound a and birinapant, and that both drugs trigger cell death through smac-mimetic compounds. however, unlike bivalent ciap1 and xiap inhibitors, smac mimetics have been shown to have mixed iap-independent and iap-dependent modes of action [ 23 ]. therefore, we suggest that the effects of iap inhibition may be determined by the relative proportion of iaps that are inhibited and therefore the magnitude of the response. future studies will be needed to elucidate the relative contributions of each of the modes of action. importantly, our modelling and validation efforts on the pdx models provide insight into the relative roles of caspase activation and inhibition in smac mimetics, which in turn will lead to improved drug design. indeed, our model was able to predict that both birinapant and compound a induce cancer cell death without measurable caspase activation.

the subcellular localization of sapc-dops is strongly correlated with its chemotoxicity, as a cytosolic marker localized sapc-dops to the cytosol in chp-100 and chp-134′ cells, whereas a mitochondrial marker localized sapc-dops to the mitochondrial compartment in the same cell lines (fig. 5a, b). together, these observations suggest that sapc-dops cytosolic localization is the major determinant of drug-responses. when performed in the cell lines chp-100 and chp-134′, these experiments revealed that, in contrast to chp-100, chp-134′ cells exhibited a mitochondrial and sapc-dops cytosolic localization. this difference in localization between chp-100 and chp-134′ cells was further confirmed by colocalization of sapc-dops with mitochondrial and cytosolic markers (figs. 5a, b, 6, 7) as well as by shift detection of oligomerization of bax protein (supplementary fig. 8). this phenomenon is highly likely to occur in chp-100 compared to chp-134′ cells, due to the difference in the location of the sapc-dops between the cell lines, shown to be highest in chp-134′ cell lines. in both cell lines, chp-134′, chp-100′, the percent of caspase 3 activation and of the smac/bax ratio, and the number of mitochondria per cell were similar, neither for chp-100 nor chp-134′ cells. while the mitochondrial marker colocalized with the fluorescent marker used to define the mitochondrial compartment in both cell lines (fig. 5d ), cyto and nuclear markers colocalized as well as defined the nucleoplasm and cytoslaves in chp-100 cells (fig. 5d ), but not in chp-134′. this discrepancy suggests that the mitochondrial localization of sapc-dops in chp-134′ cells is inherently limited.
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