To gain a more in-depth insight into the interplay between oncogenic K-Ras, tissue origin, cancer metabolic rewiring, and drug sensitivity, here, we provide evidence that K-RasG12S A549 lung cancer and K-RasG13D HCT116 colon cancer cells present substantial differences in their metabolic rewiring: as a result, the latter cell line appears to be more dependent on respiration. This evidence concerns the gene KRAS and colonic neoplasm.