Phenformin, a metformin analogue, selectively induces apoptosis in LKB1-mutant NSCLC models.
Major finding: Phenformin, a metformin analogue, selectively induces apoptosis in LKB1-mutant NSCLC models.
Mechanism: LKB1 deficiency prevents AMPK activation in response to mitochondrial complex I inhibition.
Impact: Drugs that induce metabolic stress may have antitumor activity in LKB1-mutant tumors.
The tumor suppressor LKB1 (encoded by serine/threonine kinase 11) is mutated in many human cancers, including at least 15% to 30% of non–small cell lung cancers (NSCLC). LKB1 mutation prevents activation of AMP-activated protein kinase (AMPK), a critical energy sensor that regulates cell growth and maintains energy homeostasis, resulting in impaired cellular responses to metabolic stress. Because metabolic stress induces apoptosis of LKB1-deficient cells in vitro, Shackelford and colleagues hypothesized that LKB1-mutant tumors would be sensitive to the biguanide compounds metformin and phenformin, which are used to treat diabetes and decrease ATP levels by inhibiting mitochondrial complex I. Indeed, treatment with phenformin, which is more potent and exhibits increased bioavailability, but not metformin, selectively triggered apoptosis in NSCLC cell lines lacking functional LKB1. To investigate the therapeutic potential of phenformin in vivo, the authors used genetically engineered mouse models of NSCLC driven by oncogenic Kras and deficient in either Trp53 or Lkb1. Ablation of Lkb1 blocked AMPK activation and enhanced apoptosis in lung tumors following phenformin treatment, leading to decreased tumor burden, delayed tumor progression, and prolonged survival in Lkb1-null mice compared with control and Trp53-deficient animals. The preferential antitumor activity of phenformin in Lkb1-deleted tumors was associated with a greater decrease in intracellular ATP, decreased mitochondrial function, and increased mitochondrial reactive oxygen species levels, suggesting that mitochondrial defects in the absence of LKB1 enhance the sensitivity of NSCLC cells to phenformin. Although additional studies are needed to investigate the activity and potential side effects of this drug in human cancers, these results suggest that metabolic stress-inducing drugs such as phenformin may have clinical efficacy specifically in patients with LKB1-mutant tumors.