The impact of GLP-1 receptor agonists on chemotherapeutic efficacy: insights from GWAS and experiments

Background Emerging evidence highlights the anti-tumor properties of Glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, their synergistic potential with standard chemotherapy remains largely unexplored. Methods Data from Genome-wide association study (GWAS) were used to select single-nucleotide polymorphisms (SNPs) strongly associated with lipid-lowering drug targets as instrumental variables. Causal effects were assessed primarily using the inverse variance weighted (IVW) method, supported by comprehensive sensitivity analyses to control for pleiotropy and heterogeneity. These Mendelian randomization (MR) findings were further validated through in vitro functional assays (cell viability, apoptosis, and Western blot) and an in vivo tumor-bearing mouse model. Results Glucagon-like peptide-1 receptor (GLP-1R) activity showed a significantly positive causal relationship with dihydrofolate reductase (DHFR; β = 0.323, P = 6.02 × 10 −17 ) and apoptosis regulator Bcl-2 (β = 0.259, P = 2.1 × 10 −11 ) but a negative relationship with ribonucleoside-diphosphate reductase large subunit (RRM1; β = −0.12, P = 2.32 × 10 −3 ). Functional experiments validated these genetic findings. GLP-1RA significantly enhanced the antitumoral efficacy of gemcitabine both in vitro and in vivo by repressing RRM1. Conversely, GLP-1RA attenuated the anti-tumor effects of methotrexate and paclitaxel by upregulating DHFR and Bcl-2, respectively. Notably, GLP-1RA combination therapy achieved these modulatory effects without exacerbating chemotherapy-associated systemic toxicity. Conclusion GLP1-RAs can influence the efficacy of chemotherapeutic drugs such as methotrexate, paclitaxel, and gemcitabine.