Data reported herein indicate that under chronic treatment with 5-FU, i) colon cancer cells resistant to 5-FU plastically shift their metabolism towards OXPHOS; ii) revert their addiction to a Warburg-like metabolism by inverting the ratio between PKM2 and PKM1 glycolytic enzymes; iii) this metabolic adaptation is related to the commitment of cancer cells to EMT, increased motility and achievement of stem-like traits; iv) OXPHOS inhibition, in combination with 5-FU, dramatically affects survival of resistant cells. The gene discussed is PKM; the disease is malignant colon neoplasm.