g007-lk and Skin-Neoplasms

The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy. Nevertheless, a substantial number of patients fail to respond to checkpoint pathway blockade. Evidence for WNT/β-catenin signaling-mediated immune evasion is found in a subset of cancers including melanoma. Currently, there are no therapeutic strategies available for targeting WNT/β-catenin signaling. Here we show that a specific small-molecule tankyrase inhibitor, G007-LK, decreases WNT/β-catenin and YAP signaling in the syngeneic murine B16-F10 and Clone M-3 melanoma models and sensitizes the tumors to anti-PD-1 immune checkpoint therapy. Mechanistically, we demonstrate that the synergistic effect of tankyrase and checkpoint inhibitor treatment is dependent on loss of β-catenin in the tumor cells, anti-PD-1-stimulated infiltration of T cells into the tumor and induction of an IFNγ- and CD8

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Combined Chemotherapy Protocols; beta Catenin; CD8-Positive T-Lymphocytes; Cytotoxicity, Immunologic; Drug Synergism; Enzyme Inhibitors; Female; HEK293 Cells; Humans; Immune Checkpoint Inhibitors; Interferon-gamma; Lymphocytes, Tumor-Infiltrating; Melanoma, Experimental; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Programmed Cell Death 1 Receptor; Skin Neoplasms; Sulfones; Tankyrases; Triazoles; Tumor Burden; Wnt Signaling Pathway; YAP-Signaling Proteins