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Two therapeutic targets for fatal lung cancer identified



  Two therapeutic targets for fatal lung cancer identified
The image of lung cancer shows normal lungs (light purple) and tumors (dark purple). The inactivation of SIK1
and SIK3 leads to tumor growth and inflammation, demonstrating for the first time that SIK kinases mediate key LKB1 functions in the prevention of lung cancer. Picture credits: Salk Institute

The vast majority of fatal lung cancers (85 percent) are referred to as non-small cell lung carcinoma (NSCLC), which often contains a mutant gene called LKB1. Researchers at the Salk Institute have now found out exactly why inactive LKB1 leads to carcinogenesis. The surprising results, published in the online version of Cancer Discovery on July 26, 2019, demonstrate 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 specific immediate targets for LKB1 that prevent lung cancer and, very unexpectedly, have discovered that inflammation plays a role in this tumor growth," says Professor Reuben Shaw, director of the Salk Cancer Center and senior author of the paper. "With this knowledge we can hopefully develop new therapies for this large part of lung cancer patients."

In normal functioning, LKB1 acts as a tumor suppressor and actively prevents the development of cancer. Scientists knew that the LKB1 gene functions like the captain of a relay team, relaying cellular signals, such as a baton, to enzymes called kinases, which then relay the signal to other enzymes in a chain reaction. LKB1 acts as the captain of a team of 14 different kinase team members. But which of these kinases is specifically responsible for the perception of the tumor suppressive function of LKB1 has been unclear for more than 15 years since LKB1 was first identified as a major gene disrupted in lung cancer. In 2018, the Shaw Laboratory unleashed the first step in this molecular insanity, showing that 2 out of 14 team members (the most important enzymes known to control metabolism and growth) for the effect of LKB1 on the blockade of LKB1 Surprisingly, lung cancer was not as important as most scientists had assumed. This left 12 of their kinase teammates as potentially important, but almost nothing was known about them.

"This was like a cancer detective case and we suspected that one of these 12 kinases was probably the key to the tumor-inhibiting effect of LKB1, but we were not sure which," says Pablo Hollstein, first author of the paper and postdoctoral fellow at Salk at one time and then in combinations. They observed how the inactivations influenced tumor growth and tumor development both in cell cultures of NSCLC cells and in a genetic NSCLC mouse model. The researchers pointed out the experiments to two kinases: one with the name SIK1 caused the strongest that no tumors formed. When SIK1 was inactivated, tumor growth increased; and as a related kinase, SIK3, was also inactivated, the tumor grew even more aggressive.


Salk scientists discover an enzyme pair that drives non-small cell lung cancer by promoting inflammation. Credit: Salk Institute

"The discovery that of the 14 kinases SIK1 and SIK3 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 history of is the sport, "says Shaw.

LKB1 is also known to play a role in the suppression of inflammation in cells in general. Therefore, researchers were curious to discover that SIK1 and SIK3 specifically inhibit the cellular inflammatory response in lung cancer cells. Thus, when LKB1 or SIK1 and SIK3 mutate in tumors, inflammation increases and promotes tumor growth.

In a similar way, Salk professor Marc Montminy recently co-authored with Shaw to identify metabolic switches, including SIK1 and SIK3. "Pass the baton," revealing three steps of the relay launched by LKB1.

"By attacking the problem of lung cancer from different angles, we have now defined a single direct pathway that underpins disease progression in many patients," says Dr. Shaw, who holds the William R. Brody Chair. "We've been working on this project since I started my lab in 2006. It's incredibly rewarding and amazing to find that inflammation is a driving force in tumorigenesis in this very well-defined set of lung cancers Research and how important it is to solve difficult, complicated problems, even if it takes over 10 years to find an answer. "

Next, the researchers want to continue to investigate how these kinase-induced switches trigger the lungs in inflammation Tumor growth at NSCLC.


Unlocking therapies for difficult-to-treat lung cancers


Further information:
Cancer Discovery (2019). DOI: 10.1158 / 2159-8290

Provided by
Salk Institute




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Two therapeutic targets for fatal lung cancer identified (2019, July 27)
retrieved on July 27, 2019
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