Scientists have found that a derivative of the diabetes drug metformin could hold promise for some lung cancer patients.
In studies with mice, phenformin decreased the size of lung tumours and increased the animals’ survival, scientists at the Salk Institute for Biological Studies found. The findings may give hope to the nearly 30 per cent of patients with non-small cell lung cancer (Nsclc) whose tumours lack LKB1 (also called STK11).
The LKB1 gene turns on a metabolic enzyme called AMPK when energy levels of ATP, molecules that store the energy we need for just about everything we do, run low in cells. In a previous study, Reuben Shaw, an associate professor in Salk’s Molecular and Cell Biology Laboratory demonstrated that cells lacking a normal copy of the LKB1 gene fail to activate AMPK in response to low energy levels.
LKB1-dependent activation of AMPK serves as a low-energy checkpoint in the cell. Cells that lack LKB1 are unable to sense such metabolic stress and initiate the process to restore their ATP levels following a metabolic change.
As a result, these LKB1-mutant cells run out of cellular energy and undergo apoptosis, or programmed cell death, whereas cells with intact LKB1 are alerted to the crisis and re-correct their metabolism. “The driving idea behind the research is knowing that AMPK serves as a sensor for low energy loss in cells and that LKB1-deficient cells lack the ability to activate AMPK and sense energy loss,” said David Shackelford who spearheaded the study in Shaw’s lab.
That led Shaw and his team to a class of drugs called biguanides, which lower cellular energy levels by attacking the power stations of the cell, called mitochondria. Metformin and phenformin both inhibit mitochondria; however, phenformin is nearly 50 times as potent as metformin. In the study, the researchers tested phenformin as a chemotherapy agent in genetically-engineered mice lacking LKB1 and which had advanced stage lung tumours. After three weeks of treatment, researchers saw a modest reduction in tumour burden in the mice.
