Cytidine analogs are synthetic lethal with base excision repair default due to MBD4 deficiency

Nom de la revue
npj Precision Oncology
Thomas Chabot, Fariba Nemati, Aurélie Herbette, Alexandre Demeyer, Stéphane Dayot, Olivier Ganier, Samar Alsafadi, Sophie Gardrat, Pascale Mariani, Marie Luporsi, Maxime Corbé, Vincent Servois, Nathalie Cassoux, Didier Decaudin, Sergio Roman Roman, Elaine Del Nery, Sophie Piperno-Neumann, Marc-Henri Stern, Manuel Rodrigues

AbstractInactivating mutations of MBD4 have been reported in subsets of various tumors. A deficiency of this DNA glycosylase, recognizing specifically T:G mismatch resulting from the deamination of methyl-cytosine, results in a hypermutated phenotype due to the accumulation of CpG>TpG transitions. Here, we hypothesize that the difference in DNA metabolism consecutive to MBD4 deficiency may result in specific cytotoxicities in MBD4-deficient tumor cells in a synthetic lethality fashion. After a large-scale drug repurposing screen, we show in two isogenic MBD4 knock-out cell models that the inactivation of MBD4 sensitizes cancer cells to cytidine analogs. We further confirm the exquisite activity of gemcitabine in an MBD4-deficient co-clinical model as (i) it completely prevented the development of an MBD4-deficient uveal melanoma patient-derived xenograft and (ii) treatment in the corresponding patient resulted in an exceptional tumor response. These data suggest that patients harboring MBD4-deficient tumors may be treated efficiently by cytidine analogs.