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

Inactivating 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,...

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Published in:NPJ precision oncology 2022-11, Vol.6 (1), p.81-81, Article 81
Main Authors: Chabot, Thomas, Nemati, Fariba, Herbette, Aurélie, Demeyer, Alexandre, Dayot, Stéphane, Ganier, Olivier, Alsafadi, Samar, Gardrat, Sophie, Mariani, Pascale, Luporsi, Marie, Corbé, Maxime, Servois, Vincent, Cassoux, Nathalie, Decaudin, Didier, Roman, Sergio Roman, Del Nery, Elaine, Piperno-Neumann, Sophie, Stern, Marc-Henri, Rodrigues, Manuel
Format: Article
Language:English
Subjects:
631/154/1435/2417
631/208/211
631/67/1059/99
Cancer Research
Cancer therapies
DNA methylation
DNA repair
Drugs
Gene Therapy
Genomes
Human Genetics
Internal Medicine
Medicine
Medicine & Public Health
Melanoma
Metabolism
Metabolites
Metastasis
Mutation
Oncology
Patients
Tumors
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Summary:Inactivating 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.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-022-00326-z