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Multi-drug resistance (MDR) is a curious bottleneck in cancer research and chemotherapy, whereby some cells rapidly adapt to the tumor microenvironment via a myriad of heterogeneous metabolic activities. Despite being a major impediment to treatment, there is a silver lining: control over metabolic regulation could be an effective approach to overcome or correct resistance pathways. In this critical review, we comprehensively and carefully curated and analyzed large networks of previously identified proteins associated with metabolic adaptation in MDR. We employed data and text mining to study and categorize more than 600 studies in PubMed, with particular focus on AMPK, a central and fundamental modulator in the energy metabolism network that has been specifically implicated in cancer MDR pathways. We have identified one protein set of metabolic adaptations with 137 members closely related to …