Cytidine deaminase deficiency in tumor cells is associated with sensitivity to a naphthol derivative and a decrease...

Area of Science:

• Oncology
• Biochemistry
• Pharmacology

Background:

• Cytidine deaminase (CDA) is downregulated in approximately 60% of cancers, presenting a potential therapeutic vulnerability.
• Targeting CDA-deficient tumors is a critical unmet need in cancer research.

Purpose of the Study:

• To develop a novel anticancer treatment targeting CDA-deficient tumor cells.
• To identify a specific inhibitor that preferentially affects tumor cells with low CDA expression.

Main Methods:

• High-throughput screening of a chemical library to identify CDA-targeting compounds.
• Metabolomic profiling to analyze cellular changes in response to treatment.
• Assessing the effect of the identified compound on both tumoral and non-tumoral cells.

Main Results:

• A naphthol derivative, X55, was identified as a selective inhibitor of CDA-deficient tumor cells.
• X55 treatment significantly disturbed the metabolome of CDA-deficient cells, impacting oncometabolite levels.
• Downregulation of MAPT (encoding Tau) was identified as a predictive marker for X55 sensitivity.

Conclusions:

• X55 demonstrates potential as a targeted therapy for CDA-deficient cancers.
• CDA deficiency, mitochondrial function, and X55 response are unexpectedly linked.
• MAPT downregulation serves as a reliable biomarker for predicting X55 efficacy.