Cancer cells utilize altered bioenergetics to fuel uncontrolled proliferation and progression. At the core of bioenergetics, adenine nucleotides are the building blocks for nucleotide synthesis, energy transfer and diverse metabolic processes. Adenylate kinases (AK) are ubiquitous phosphotransferases that catalyze the conversion of adenine nucleotides and regulate the homeostasis of nucleotide ratios within cellular compartments. Recently, different isoforms of AK have been shown to induce metabolic reprograming in cancer and were identified as biomarkers for predicting disease progression. Here we aim to systemically analyze the impact of all AK-associated gene signatures on lung adenocarcinoma patient survival and decipher the value for therapeutic interventions. By analyzing TCGA Lung Adenocarcinoma (LUAD) RNA Seq data, we found gene signatures from AK4 and AK1 have higher percentage of prognostic genes compared to other AK-gene signatures. A 118-gene signature was identified from consensus gene expression in AK1 and AK4 prognostic gene signatures. Immunohistochemistry (IHC) analyses in 140 lung adenocarcinoma patients showed overexpression of AK4 significantly correlated with worse overall survival (P = 0.001) whereas overexpression of AK1 significantly associated with good prognosis (P = 0.009). Furthermore, reduced AK4 expression by shRNA reduced the EGFR protein expression in EGFR mutation cells. The inhibition of AK4-AK1 signal might provide a potential target for synergistic effect in target therapy in lung cancer patients.