Abstract IA23: Marker-guided targeted therapy, PARP inhibitors, and novel post-translational modification of PD-L1
Authors: Hung Mien-Chie 
Published: June 2021

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. Three PARP inhibitors have been approved by the FDA to treat ovarian cancer with (olaparib and rucaparib) or without BRCA mutations (niraparib). BRCA1 and BRCA2 play essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. My group recently demonstrated that receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907. Phosphorylation of PARP1 Tyr907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. Combining c-Met and PARP1 inhibitors synergized to suppress growth of breast cancer cells in vitro and xenograft tumor models. Similar synergistic effects were observed in a lung cancer xenograft tumor model. These results suggest that PARP1 pTyr907 abundance may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients bearing tumors with high c-Met expression who do not respond to PARP inhibition alone (Nature Medicine 2016;22:194). We are working with clinicians at MD Anderson to initiate marker-guided clinical trials using combinational therapy of PARP and c-MET inhibitors. Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumor-associated immune escape. We further explored whether a cross-talk exists between PARP inhibition and PD-L1/PD-1 immune checkpoint axis and determined whether blockade of PD-L1/PD-1 potentiates PARP inhibitor (PARPi) in tumor suppression. PARP inhibitor (PARPi) treatment upregulates tumor cell PD-L1 expression, which attenuates PARPi efficacy via cancer-associated immunosuppression. The blockade of PD-L1 can restore the attenuated antitumor immunity and potentiate PARPi in tumor suppression (Clinical Cancer Res 2017;23:3711).

My group also conducted a highly translational study, which identified a link between the ubiquitination and glycosylation pathways that regulate the immunosuppressive activity of PD-L1 (Nature Communications 2016;7:12632). We showed that glycosylation of PD-L1 is required for its protein stability and interaction with PD-1. In addition, we demonstrated that metformin-activated AMPK kinase downregulates PD-L1 through phosphorylation of Ser-195, which alters glycosylation of PD-L1 and functionally mimics anti-PD-L1 to block PD-L1/PD-1 interaction. It exhibited a highly potent synergistic effect of combination therapy of metformin, a drug that has been used to treat patients with diabetes and anti-CTLA4. The therapeutic efficacy could reach to survival rate of 50-70% in different syngeneic mouse models, which were treated by this combination therapy (Molecular Cell 2018;71:606). We also demonstrated that epithelial-mesenchymal transition (EMT) enhances PD-L1 in cancer stem-like cells (CSCs) by the EMT/β-catenin/STT3-PD-L1 signaling axis. Etoposide, a commonly used anticancer chemotherapy drug, is able to suppress this signaling axis, resulting in downregulation of PD-L1 to sensitize cancer cells to anti-Tim 3 therapy (Nature Communications 2018;9:1908). These findings provide potential therapeutic strategies to enhance cancer immune therapy efficacy by targeting PD-L1 stabilization to combat multiple cancer types. We identified TNFα as a major factor triggering cancer cell immunosuppression against T-cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1) (Cancer Cell 2016;30:925). To this end, in collaboration with StCube Pharmaceuticals Inc., we have developed monoclonal antibodies against glycosylation-specific PD-L1. Impressive therapeutic effect was observed through antibody-drug-conjugate approach (Cancer Cell 2018;33:187). Most recently, we unraveled an active defense system of PD-L1, previously known to only associate with passive defense activity. We discovered that cancer cells that express PD-L1 can secrete exosomes containing PD-L1 (exosome-PD-L1). The exosome-PD-L1 is able to directly interact with PD-1 to inhibit T-cell activation as well as T-cell killing activity (Cell Res 2018;28:862). Our new discoveries provide a new means to enhance therapeutic efficacy of immune checkpoint therapy.

Citation Format: Mien-Chie Hung. Marker-guided targeted therapy, PARP inhibitors, and novel post-translational modification of PD-L1 [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA23.