LAUSR

Melanoma is an aggressive neoplasm with increasing incidence that bears the infamous distinction of being a recalcitrant cancer, i.e. a cancer with poor prognosis, lacking progress in diagnosis and treatment. In addition to conventional therapy, melanoma treatment is currently based on targeting the BRAF/MEK/ERK signal transduction pathway and immune checkpoints; however, advanced therapeutic approaches based on novel targets are urgently needed. We reasoned that the base excision repair enzyme Thymine DNA Glycosylase (TDG) could be such a target for its dual role in safeguarding genome stability and in effecting active DNA demethylation downstream the Ten-Eleven Translocation (TET) dioxygenases. TDG knockdown in melanoma cell lines causes cell cycle arrest, senescence and death by mitotic alterations, and impairs xenograft formation. Importantly, untransformed melanocytes are not affected by TDG knockdown, and adult mice with conditional knockout of TDG are viable. Candidate TDG inhibitors, identified through a high-throughput screen, reduced viability and clonogenic capacity of melanoma cell lines. Candidate TDG inhibitors increased cellular levels of 5-carboxylcytosine, the last intermediate in DNA demethylation, which is specifically removed by TDG, indicating successful targeting. These findings suggest that TDG may provide critical functions in cancer cells, but not in normal cells, that make it a highly suitable anti-melanoma drug target. By potentially disrupting both DNA repair and the epigenetic state, targeting TDG may represent a completely new approach to melanoma therapy. Citation Format: Rossella Tricarico, Pietro Mancuso, Vikram Bhattacharjee, Laura Cosentino, Emmanuelle Nicolas, Margret Einarson, Neil Beeharry, Karthik Devarajan, Rich Katz, Dorjbal G. Dorjsuren, Anton Simeonov, Yuwaraj Kadariya, Guillaume Davidson, Joseph R. Testa, Irwin Davidson, Lionel Larue, Robert W. Sobol, Timothy Yen, Alfonso Bellacosa. Thymine DNA glycosylase (TDG) as a novel target for melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1940.