Round 85% of deadly lung cancer cases are referred to as non-small-cell lung carcinomas (NSCLCs), which often contain a mutated gene called LKB1. Researchers have just discovered precisely why inactive LKB1 results in cancer development. The results, published in Cancer Discovery, highlight the way in which LBK1 communicates with two enzymes that suppress inflammation in addition to cell growth, to block tumour growth.

For the first time, we've found specific direct targets for LKB1 that prevent lung cancer and discovered–very unexpectedly–that inflammation plays a role in this tumour growth,” says Professor Reuben Shaw, director of the Salk Cancer Centre and senior author of the paper. “With this knowledge we can hopefully develop new treatments for this large fraction of lung cancer patients.”

When functioning normally, LKB1 acts as a tumour suppressor, preventing cancer from forming. Scientists knew that the LKB1 gene worked like the captain of a relay team, passing cellular signals, like a baton, to enzymes called kinases, which then passed the signal to other enzymes in a chain reaction. However, which of these kinases is specifically responsible for carrying on LKB1's tumour suppressive function was unknown for more than 15 years since LKB1 was first identified as a major gene disrupted in lung cancer.

To figure it out, the team used CRISPR technology combined with genetic analysis to inactivate each suspected kinase one at a time and then in combinations. They observed how these affected tumour growth and development in both cell cultures of NSCLC cells and in a genetic NSCLC model. The experiments pointed towards two kinases: SIK1 and SIK3.

“By attacking the problem of lung cancer from different angles, we have now defined a single direct route that underpins how the disease develops in many patients,” says Shaw. “This discovery highlights the nature of scientific research and how important it is to commit to pursuing difficult, complicated problems, even if it takes over 10 years to get an answer.”