nu-7441 and Melanoma

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Despite of important progress in the local therapy, high radioresistance in primary tumor and chemoresistance in metastatic disease are the major obstacles for UM therapy. Therefore, strategies to overcome resistance to radiation or chemotherapy in UM are urgently needed. In this study, we found that phosphorylation of DNA-PKcs, which is the key factor of non-homologous end joining (NHEJ) pathway, was remarkably overexpressed in ionizing radiation (IR)- and Selumetinib resistant UM cells. Increased amount of NHEJ events were also observed in resistant UM cells. Inhibition of DNA-PKcs by NU7441 significantly impaired DNA repair and re-sensitized resistant UM cells to radiation and Selumetinib both in vitro and in vivo. The results demonstrate increased DNA double strand break repair as a mechanism of resistance to ionizing radiation and Selumetinib, and identify DNA-PKcs as a promising target for radio-and chemotherapy in UM patients.

Topics: Animals; Benzimidazoles; Cell Line, Tumor; Chromones; DNA-Activated Protein Kinase; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Humans; Melanoma; Mice, Inbred BALB C; Morpholines; Phosphorylation; Radiation-Sensitizing Agents; Uveal Neoplasms

Combination therapies have the potential to improve outcomes in melanoma patients but have not yet been clinically efficacious. Here, we used high-throughput flow cytometry-based screening to identify and characterize candidate therapies that might synergize with and augment T-cell immunotherapy efficacy. Two lead therapies, regorafenib (Reg) and NU7441, were selected based on their ability to alter a variety of immunomodulatory proteins, including CD55, CD73, CD155, programmed death-ligand 1 (PD-L1), nerve growth factor receptor (NGFR), and HLA class I in a heterogeneous panel of melanomas. The therapies also upregulated several melanoma antigens, inhibited proliferation, and perturbed activation of oncogenic signaling pathways in melanomas. T cells treated with the therapies proliferated normally and exhibited a favorably altered phenotype, including increased CD25, CD28, inducible T-cell costimulator (ICOS), and reduced expression of coinhibitory receptors. Cytokine production was also increased in treated T cells. When administered in mice, REg suppressed melanoma progression in a CD8

Topics: 5'-Nucleotidase; Animals; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; CD55 Antigens; CD8-Positive T-Lymphocytes; Cell Proliferation; Chromones; Flow Cytometry; Genes, MHC Class I; Humans; Immunomodulation; Immunotherapy; Melanoma; Mice; Morpholines; Phenylurea Compounds; Pyridines; Receptors, Virus; T-Lymphocyte Subsets; Tumor Microenvironment