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Bladder cancer is among the top ten most common cancers, with about ~380,000 new cases and ~150,000 deaths per year worldwide. Tumor relapse following chemotherapy treatment has long been a significant challenge towards completely curing cancer. We have utilized a patient-derived bladder cancer xenograft (PDX) platform to characterize molecular mechanisms that contribute to relapse following drug treatment in advanced bladder cancer. Transcriptomic profiling of bladder cancer xenograft tumors by RNA-sequencing analysis, before and after relapse, following a 21-day cisplatin/gemcitabine drug treatment regimen identified methionine adenosyltransferase 1a (<i>MAT1A</i>) as one of the significantly upregulated genes following drug treatment. Survey of patient tumor sections confirmed elevated levels of <i>MAT1A</i> in individuals who received chemotherapy. Overexpression of <i>MAT1A</i> in 5637 bladder cancer cells increased tolerance to gemcitabine and stalled cell proliferation rates, suggesting <i>MAT1A</i> upregulation as a potential mechanism by which bladder cancer cells persist in a quiescent state to evade chemotherapy.