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

Area of Science:

• Genetics and Genomics
• Cancer Biology
• Drug Discovery

Background:

• Inactivating mutations in MBD4 are found in various cancers.
• MBD4 deficiency leads to a hypermutated phenotype by increasing CpG>TpG transitions.
• This suggests MBD4-deficient tumors may have unique metabolic vulnerabilities.

Purpose of the Study:

• To investigate the potential of synthetic lethality in MBD4-deficient cancer cells.
• To identify drugs that specifically target MBD4-deficient tumors.

Main Methods:

• Large-scale drug repurposing screen.
• Utilized isogenic MBD4 knock-out cell models.
• Tested gemcitabine in an MBD4-deficient uveal melanoma patient-derived xenograft and in a patient.

Main Results:

• MBD4 inactivation sensitizes cancer cells to cytidine analogs.
• Gemcitabine demonstrated complete prevention of tumor development in an MBD4-deficient xenograft model.
• Exceptional tumor response was observed in a patient with MBD4-deficient uveal melanoma treated with gemcitabine.

Conclusions:

• MBD4 deficiency creates a synthetic lethal vulnerability to cytidine analogs.
• Gemcitabine is a promising therapeutic option for MBD4-deficient tumors, including uveal melanoma.
• Targeting MBD4-deficient tumors with cytidine analogs warrants further clinical investigation.