| Title: |
Cytidine analogs are synthetic lethal with base excision repair default due to MBD4 deficiency. |
| 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 |
| Source: |
NPJ Precision Oncology; 11/2/2022, Vol. 6 Issue 1, p1-9, 9p |
| Subject Terms: |
DRUG repositioning, UVEA cancer, DEAMINATION, CANCER cells |
| Abstract: |
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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
