Repression of LKB1 bymiR-17∼92sensitizesMYC-dependent lymphoma to biguanide treatment

Cancer cells display metabolic plasticity to survive metabolic and energetic stresses in the tumor microenvironment, prompting the need for tools to target tumor metabolism. Cellular adaptation to energetic stress is coordinated in part by signaling through the Liver Kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Reducing LKB1-AMPK signaling exposes metabolic vulnerabilities in tumor cells with potential for therapeutic targeting. Here we describe that miRNA-mediated silencing of LKB1 (mediated by the oncogenic miRNA clustermiR-17∼92) confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and novel (IM156) biguanides, we demonstrate thatMyc+lymphoma cells with elevatedmiR-17∼92expression display increased sensitivity to biguanide treatment both in cell viability assaysin vitroand tumor growth assaysin vivo. This increased biguanide sensitivity is driven bymiR-17-dependent silencing of LKB1, which results in reduced AMPK activation in response to bioenergetic stress. Mechanistically, biguanide treatment inhibits TCA cycle metabolism and mitochondrial respiration inmiR-17∼92-expressing tumor cells, targeting their metabolic vulnerability. Finally, we demonstrate a direct correlation betweenmiR-17∼92expression and biguanide sensitivity in human cancer cells. Our results identifymiR-17∼92expression as a potential biomarker for biguanide sensitivity in hematological malignancies and solid tumors.One Sentence SummarymiR-17∼92 expression inMyc+tumors sensitizes cancer cells to biguanide treatment by disrupting bioenergetic stability in lymphoma cells.