Identification Of Potentially Predictive Biomarkers For Tumor Sensitivity To Proapoptotic Receptor Agonists

14505 Background: Apo2L/TRAIL selectively stimulates cancer-cell death through the proapoptotic receptors DR4 and DR5. Endogenous Apo2L/TRAIL is expressed on natural killer cells and has been implicated in immune surveillance against metastatic tumor cells. We have generated two proapoptotic receptor agonists (PARAs) as experimental cancer- therapeutic agents: soluble recombinant human (rh)Apo2L/TRAIL, which induces apoptosis through DR4 and/or DR5; and Apomab-a fully human, affinity-matured agonistic antibody that triggers apoptosis through DR5. Both PARAs display antitumor efficacy and cooperate with various chemotherapy and other agents in diverse cancer xenograft models. Systemic infusion of either PARA is well tolerated in non-human primates, and both molecules are currently in clinical trials. Methods: To identify potential determinants of tumor susceptibility to rhApo2L/TRAIL, we characterized a panel of cancer cell lines for sensitivity to the ligand in relation to gene expression profiles. Results: mRNA expression of the peptidyl O-glycosyl transferase GALNT14 correlated with rhApo2L/TRAIL sensitivity in pancreatic carcinoma, non-small cell lung carcinoma and melanoma cell lines (P < 9X10−6; n=83), and up to 30% of primary tumor samples from various human malignancies displayed GALNT14 overexpression. Loss- and gain-of function experiments revealed that GALNT14 promotes O-glycosylation of DR4 and DR5; this modification facilitated ligand- stimulated receptor clustering, to mediate recruitment and activation of the apoptosis-initiating protease caspase-8. Conclusion: These results uncover a novel link between O-glycosylation of cell-surface receptors and apoptosis signaling, providing potentially predictive biomarkers for PARA-based cancer therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology