New DNA repair inhibitors for melanoma treatment: a study of combined treatment with Dbait and DTIC

Uveal melanoma (UM) and cutaneous melanoma (CM) are distinct entities, but with the same poor response to systemic treatment and radiotherapy leading to frequent symptomatic locoregional recurrence and distant metastasis. . A transcriptome analysis of both these groups of melanomas revealed that the DNA-PK gene was overexpressed in metastasis and potentially involved in tumor development and treatment resistance. We have designed an innovative family of molecules known as Dbait (for DNA bait), which enhance DNA-damaging treatments by interfering with DNA repair. Dbait induces a "false" DNA damage signal through DNA-PK activation, preventing DNA repair by hindering the further recruitment of DNA repair enzymes to damage sites. We found that Dbait administration alone slowed tumor growth in MM26 (UM) and SK28 (CM) tumor models. However, it increased sensitivity to DTIC in MM26 melanoma, but not in the highly resistant MP41 and SK28 melanomas.