Figure 9.

Schematic representation of the proposed therapeutic strategy to improve the efficacy of PKM targeting therapy in cancer cells in the background of the cellular status of the LKB1-AMPK pathway. A, the effect of the bioenergetic sensor, LKB1-AMPK signaling on cellular metabolic pathways to preserve energy homeostasis. B, the pro-growth metabolic phenotype of tumor cells that lacks or expresses a nonfunctional LKB1 (i.e. somatic mutation, promoter hypermethylation, or exonic deletion) and thus fails to activate the bio-energetic sensor AMPK. C, the therapeutic efficacy of PKM2 or PKM1 silencing in tumor cells that lack LKB1-AMPK signaling pathway to rewire metabolic phenotype and to restore the perturbed ATP level. D, the metabolic phenotype of tumor cells that possess the intact bio-energetic sensors, LKB1-AMPK signaling pathway. E, the mechanistic insight of LKB1-AMPK mediated metabolic rewiring and the restored energy homeostasis that confers treatment resistance against PKM silencing in cancer cells. F, the proposed therapeutic scheme of inducing synthetic lethality in cancer cells by targeting the pro-growth metabolism by silencing PKM isoforms and reducing resistance toward apoptosis by targeting the AMPK pathway.