Two therapeutic targets identified for deadly lung cancer

Home >> News Center >> Two therapeutic targets identified for deadly lung cancer

Two therapeutic targets identified for deadly lung cancer

Salk scientists discover a pair of enzymes that drive non-small-cell lung cancer by promoting inflammation

The vast majority of fatal lung cancer cases (85%) are called non-small cell lung carcinomas (NSCLCs), which often contain a mutated gene called LKB1. Researchers at the Salk Institute have now discovered precisely why inactive LKB1 causes cancer development. The surprising results, published in the online version of Cancer Discovery on July 26, 2019, highlight how LBK1 communicates with two enzymes that suppress inflammation in addition to cell growth to block tumor growth. The results could lead to new therapies for NSCLC.

"For the first time, we have found direct targets specific to LKB1 that prevent lung cancer and unexpectedly discovered that inflammation plays a role in the growth of this tumor," says Professor Reuben Shaw, Director of the Salk Cancer Center and lead author of the document. "With this knowledge, we can hopefully develop new treatments for this large proportion of lung cancer patients."

When used normally, LKB1 acts as a tumour suppressor, actively preventing the formation of cancer. Scientists knew that the LKB1 gene functioned as the captain of a relay team, transmitting cellular signals, like a stick, to enzymes called kinases, which then transmitted the signal to other enzymes in a chain reaction. LKB1 is the captain of a team of 14 different kinase teammates. But which of these kinases is specifically responsible for the suppressive function of LKB1 tumor has not been clear for more than 15 years since LKB1 was first identified as a major disrupted gene in lung cancer. In 2018, the Shaw Laboratory solved the first stage of this molecular whodunnit by showing that 2 of the 14 teammates (the main enzymes known to control metabolism and growth) were not surprisingly not as important for the effects of LKB1 on lung cancer as most scientists had thought. So there were 12 of their kinase teammates left as potentially important, but almost nothing was known about them.

"It was like a cancer case. We suspected that one of these 12 kinases was probably the key to the anti-tumor effects of LKB1, but we didn't know which one," explains Pablo Hollstein, the first author of the article and a postdoctoral fellow at Salk.

To find out, the team used CRISPR technology combined with genetic analysis to inactivate each suspected kinase one at a time and then in combination. They observed how inactivations affected tumor growth and development in both cell cultures of NSCLC cells and in a genetic NSCLC mouse model. The experiments identified two kinases: one called SIK1 had the most important effect in preventing tumor formation. When SIK1 was inactivated, tumor growth increased; and when a related kinase, SIK3, was also inactivated, the tumor increased even more aggressively.

"To discover that of the 14 kinases, SIK1 and SIK3 were the most critical players, is like discovering that the relatively unknown reserve quarterback who almost never plays is actually one of the most important quarterbacks in the history of the sport," Shaw said.

LKB1 is also known to play a role in suppressing inflammation in cells in general, so researchers were intrigued to discover that SIK1 and SIK3 specifically inhibited the cellular inflammatory response in lung cancer cells. Thus, when LKB1 or SIK1 and SIK3 mutate in tumours, inflammation increases, stimulating tumour growth.

In the same vein, Professor Marc Montminy, Professor at Salk University, recently published, in collaboration with Shaw, an article identifying the metabolic changes to which SIK1 and SIK3 "pass the baton", revealing three stages of the relay launched by LKB1.

"By tackling lung cancer from different angles, we have now defined a single direct pathway that underlies the disease progression in many patients," says Shaw, William R. Brody Chairholder. "We have been working on this project since I started my laboratory in 2006, so it is incredibly rewarding and surprising to see that inflammation is a driving force in the formation of tumours in this very clearly defined set of lung cancers. This discovery highlights the nature of scientific research and the importance of committing to pursue difficult and complicated problems, even if it takes more than 10 years to get an answer."

Next, the researchers intend to investigate in more detail how these kinase-activated switches in inflammation trigger the growth of lung tumours in NSCLC.