A break in the case

Two enzymes indicted in inflammation and tumor growth in non-small cell lung carcinomas

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LA JOLLA, Calif.—Researchers at the Salk Institute for Biological Studies made a surprising discovery of two enzymes that play a critical role in the cellular inflammation response in lung cancer cells. The discovery, shared in a paper published online in Cancer Discovery, provides new insights into enzymes that affect tumor growth in deadly non-small cell lung cancers and suggests exciting new potential targets for therapeutic intervention.
Non-small cell lung carcinomas (NSCLCs) often contain a mutated gene called LKB1; the gene’s connection to cancer growth has been acknowledged for nearly 15 years, but its exact role has remained a mystery.
“In healthy cells and tissues, LKB1 controls the function of 14 other enzymes, but the potential roles and functions of these 14 enzymes has not been completely clear, especially what roles they might have in suppressing cancer,” says Dr. Pablo E. Hollstein, postdoctoral fellow at the Salk Institute and lead author of the article. “Our lab has been working to understand the relationship between LKB1 and these 14 enzymes since 2006, and over this time, we have gained incremental understanding of both the roles and functions of LKB1 and its team of enzymes in both the context of healthy cells and tissues and in cancer.”
As part of a sequence of experiments spanning more than a decade, the research team used CRISPR technology combined with genetic analysis to systematically deactivate each of the enzymes controlled by LKB1 in turn, and then, in various combinations, to observe the effect on tumor growth and development in cell cultures and in a mouse model.
In 2018, the lab eliminated two of the “suspects,” discovering that two of the 14 enzymes that LKB1 controls were not, in fact, linked to suppressing cancer, leaving open the question of which of the remaining 12 possible targets could be responsible for preventing the growth of cancer cells.
In 2019, the team made a surprisingly clear discovery. One of the enzymes controlled by LKB1—a kinase called SIK1—showed the strongest effect in stopping tumors from forming. When SIK1 was inactivated, tumor growth increased. In addition, when a related kinase called SIK3 was also inactivated, tumors grew even more aggressively. Thus, when LKB1 or SIK1 and SIK3 become mutated in tumors and cease to function, inflammation is increased, driving tumor growth.
According to Hollstein, “This was a very surprising finding. Finding out that SIK1 and SIK3 together out of the 12 remaining enzymes were the ones responsible to keep lung cancer in check would not have been predicted based on the existing knowledge about these enzymes at the time. In particular, the observation that SIK1 and SIK3 inhibit the kind of cellular inflammation that can fuel the growth of tumors in lung tissues was a complete surprise.”
“Discovering that of the 14 kinases it was SIK1 and SIK3 that were the most critical players is like discovering that the relatively unknown backup quarterback who almost never plays is actually one of the most important quarterbacks in the history of the sport,” explained Prof. Reuben Shaw, director of the Salk Cancer Center and senior author of the paper.
The discovery opens a path to conduct further research on these potential therapeutic targets in a patient cohort with serious unmet needs.
“We now have a clear and rational avenue to explore therapies that we hope will be beneficial for the subset of patients with lung cancer who have LKB1 mutations or otherwise have non-functioning SIK1 and SIK3,” says Hollstein. “For example, strategies aimed at reducing the specific kind of inflammation that fuels cancer cell growth in the absence of functional LKB1 or SIK1 and SIK3 may reduce or stop cancer cell growth in these patients. Additionally, small-molecule therapies could be used to neutralize proteins that promote this pro-inflammatory process when LKB1 or SIK1 and SIK3 are not functioning.”
According to Hollstein, about 85 percent of deadly lung cancers are non-small cell lung cancers (NSCLCs), and LKB1 is inactivated in a significant proportion of these. Its loss contributes to the development and the aggressiveness of these cancers.
“Many NSCLC patients do not respond well to conventional therapies because their lung cancers are resistant to these therapies,” he comments. “In particular, the subset of patients whose cancers have undergone mutation of LKB1 would benefit greatly from therapies aimed at restoring some of the functions to restrain or stop cancer growth that LKB1, SIK1 and SIK3 have.
“Notoriously, lung cancers with LKB1 mutations can be resistant to conventional therapies and unfortunately are also resistant to some of the newer immune checkpoint therapies that are being tested in the clinic today,” Hollstein adds. “The finding that SIK1 and SIK3 work to prevent lung cancer growth by restraining inflammation suggests that strategies that block this kind of inflammation may be beneficial in NSCLC cancers.”

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