Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) has raised attention as a novel anticancer therapeutic as it induces apoptosis preferentially in
tumor cells. However, first-generation TRAIL-receptor agonists (TRAs), comprising recombinant TRAIL and agonistic receptor-specific
antibodies, have not demonstrated anticancer activity in clinical studies. In fact,
cancer cells are often resistant to conventional TRAs. Therefore, in addition to TRAIL-sensitizing strategies, next-generation TRAs with superior apoptotic activity are warranted.
APG350 is a novel, highly potent TRAIL-receptor agonist with a hexavalent binding mode allowing the clustering of six
TRAIL-receptors per drug molecule. Here we report on preclinical in vitro and in vivo studies testing the activity of
APG350 on pancreatic ductal
adenocarcinoma (PDAC) cells. We found that
APG350 potently induced apoptosis of Colo357, PancTuI and Panc89 cells in vitro. In addition,
APG350 treatment activated non-canonical TRAIL signaling pathways (
MAPK, p38, JNK, ERK1/ERK2 and NF-κB) and induced the secretion of
IL-8. Stable overexpression of Bcl-xL inhibited APG350-induced cell death and augmented activation of non-canonical pathways. Intriguingly, pre-treatment of Bcl-xL-overexpressing cells with the BH3-mimic
Navitoclax restored their sensitivity to
APG350. To study the effects of
APG350 on PDAC cells in vivo, we applied two different orthotopic
xenotransplantation mouse models, with and without primary
tumor resection, representing adjuvant and
palliative treatment regimes, respectively.
APG350 treatment of established
tumors (
palliative treatment) significantly reduced
tumor burden. These effects, however, were not seen in
tumors with enforced overexpression of Bcl-xL. Upon primary
tumor resection and subsequent
APG350 treatment (adjuvant
therapy),
APG350 limited recurrent
tumor growth and
metastases. Importantly, therapeutic efficacy of
APG350 treatment was more effective compared with treatment with soluble TRAIL in both models. In conclusion,
APG350 represents a promising next-generation TRA for the treatment of PDAC. Moreover, our results suggest that combining
APG350 with
Navitoclax might be a succesfull strategy for
cancers harboring mitochondrial apoptosis resistance.