ARID1A Deficiency in Diffuse-Type Gastric Cancer Promotes a Pyrimidine Metabolic Vulnerability

Area of Science:

• Oncology
• Metabolic pathways
• Cancer genetics

Background:

• Loss-of-function mutations in ARID1A characterize an aggressive diffuse gastric cancer (DGC) subtype.
• This DGC subtype often displays resistance to conventional chemotherapy.

Purpose of the Study:

• To identify a specific metabolic vulnerability in ARID1A-deficient DGC.
• To explore the potential of Gemcitabine as a targeted therapy for ARID1A-deficient DGC.

Main Methods:

• Integrated metabolomic and transcriptomic analyses were performed.
• The role of the nucleoside transporter SLC28A3 and its impact on deoxycytidine pools were investigated.
• Gemcitabine's mechanism of action in ARID1A-deficient cells was elucidated.
• Ex vivo patient-derived cultures and in vivo peritoneal dissemination models were utilized for validation.

Main Results:

• ARID1A loss leads to transcriptional repression of SLC28A3, creating a reliance on this transporter for deoxycytidine (dC) uptake.
• ARID1A deficiency results in a significant "low-dCTP" metabolic bottleneck.
• Gemcitabine effectively targets these cells by entering through equilibrative transporters (ENTs) and exerting a dual-hit effect: inhibiting nucleotide synthesis and competing for DNA incorporation.
• The synergistic collapse of pyrimidine metabolism was confirmed in preclinical models.

Conclusions:

• ARID1A-deficient DGC exhibits a unique metabolic vulnerability linked to SLC28A3 transporter function.
• Repurposing Gemcitabine presents a promising precision medicine strategy for treating ARID1A-deficient gastric cancer.