Co-Targeting of DTYMK and PARP1 as a Potential Therapeutic Approach in Uveal Melanoma

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 16; p. 1348
• Main Authors: Oziębło, Sylwia, Mizera, Jakub, Górska, Agata, Krzyziński, Mateusz, Karpiński, Paweł, Markiewicz, Anna, Sąsiadek, Maria Małgorzata, Romanowska-Dixon, Bożena, Biecek, Przemysław, Hoang, Mai P, Mazur, Antonina J, Donizy, Piotr
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.08.2024; MDPI
• Subjects: Analysis; BAP1; Cancer; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cytotoxicity; DNA repair; DTYMK; Enzymes; Ethylenediaminetetraacetic acid; Gene expression; Genomes; Humans; Immunohistochemistry; inhibitors; Kinases; Medical prognosis; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Metabolism; Metastasis; PARP1; Physiological aspects; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Prognosis; Proteins; Signal transduction; Signal Transduction - drug effects; Therapeutic targets; TOR protein; Tumor cell lines; Tumors; uveal melanoma; Uveal Neoplasms - drug therapy; Uveal Neoplasms - metabolism; Uveal Neoplasms - pathology; Poland; Germany; United States > US; inhibitors; DTYMK; PARP1; uveal melanoma; intraocular tumor; immunohistochemistry; BAP1
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13161348

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, with no standardized treatment for advanced disease. Based on preliminary bioinformatical analyses DTYMK and PARP1 were selected as potential therapeutic targets. High levels of both proteins were detected in uveal melanoma cells and correlated with increased tumor growth and poor prognosis. In vitro tests on MP41 (BAP1 positive) and MP46 (BAP1 negative) cancer cell lines using inhibitors pamiparib (PARP1) and Ymu1 (DTYMK) demonstrated significant cytotoxic effects. Combined treatment had synergistic effects in MP41 and additive in MP46 cell lines, reducing cell proliferation and inhibiting the mTOR signaling pathway. Furthermore, the applied inhibitors in combination decreased cell motility and migration speed, especially for BAP1-negative cell lines. Our hypothesis of the double hit into tumoral DNA metabolism as a possible therapeutic option in uveal melanoma was confirmed since combined targeting of DTYMK and PARP1 affected all tested cytophysiological parameters with the highest efficiency. Our in vitro findings provide insights into novel therapeutic avenues for managing uveal melanoma, warranting further exploration in preclinical and clinical settings.