FPGS (Folylpolyglutamate Synthase)

For over 70 years, methotrexate (MTX) has remained a first-line chemotherapeutic agent for acute lymphoblastic leukemia (ALL), playing a pivotal role in maintenance therapy...Mechanistically, dual-luciferase reporter and electrophoretic mobility shift assays revealed that rs1544105 A > G enhanced the binding affinity of the SNP-containing sequence for the transcription factor CREB1, thereby increasing FPGS transcriptional activity and ultimately augmenting MTX efficacy. Our multidimensional study, integrating data analysis with cellular, molecular, and animal experiments, highlights the remarkable regulatory role of a single SNP, rs1544105, in modulating MTX therapeutic response and provides a basis for individualized MTX-based maintenance therapy in ALL patients.

These patients with high FPG_Score were more likely to benefit from immunotherapy and had a more favorable prognosis. Our study innovatively provided a comprehensive analysis of FPGs in GC, and constructed the FPG_Score system for stratification of individual patients, so as to predict its benefit from immunotherapy and prognosis.

MTX resistance in relapsed ALL relies on FPGS inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL.

MIA PaCa-2 pancreatic cancer cells with CRISPR knockout of FPGS were engineered to express doxycycline-inducible FPGS exclusively in the cytosol (cFPGS) or in both the cytosol and mitochondria (mFPGS)...AGF347 accumulation increases with folylpolyglutamate synthetase (FPGS) levels in both the cytosol and mitochondria. Increased mitochondrial FPGS stimulated one-carbon metabolic fluxes in the cytosol and mitochondria and substantially enhanced in vitro inhibition of pancreatic cancer cells by AGF347 Mitochondrial FPGS levels play important roles in determining the anti-tumor efficacies of pyrrolo[3,2-d]pyrimidine antifolates for pancreatic cancer.