Recently, researchers at the Salk Institute in the United States found that by maintaining a cell "switch" called CREB, tumorgrowth can be triggeredThe drug that blocks this "switch" may offer life-long hope for non-small cell lung cancer patientsDOI: 10.1126/sciadv.aaw6455in fact, non-small cell lung cancer does not currently have a good and definitive effective treatment, and this study may be a major breakthrough for the disease"switch molecule" CREB
The CREB molecule is a transcription factor that binds to DNA to alter gene transcription and plays a key role in protein manufacturingSalk Labs' Montminy and Shaw Labs have focused on the role of CREB in diabetesBut in recent years, a growing body of research has shown that CREB is also important in cancerLaura Rod?n, from The Montminy Laboratory, wanted to see which genes bind to specific CREBs and non-small cell lung cancer patients to see how CREB affects cancer and reveal potential new drug targetsSo the team studied the growth of non-small cell lung cancer cells in mouse models and compared the laboratory results with patient tumor dataThe researchers found that CREB and its partner CRTC2 were activated in a subgroup of non-small cell lung cancerCREB and its partner CRTC2 are activated in non-small cell lung cancerThe images showed that the lung tumors (dark purple) in the control group compared to those in the mice lacking CRTC2 (bottom), indicating that drugs interfering with CREB or CRTC2 had therapeutic potential in this segment of the patientsLKB1dereliction of duty LKB1 is a tumor suppressor that should normally actively block this activationBut the checkpoint disappeared in patients with genetic mutationsIn these patients, CRTC2 is abnormally activated and stimulates the genes that cause lung cancer More notably, follow-up experiments by the team showed that CRTC2 had mistakenly started another gene called ID1, which is known to cause cancer in other tissues the LKB1 gene works like a relay team captain, passing cell signals to kinases like a baton and then passing them through a chain reaction to other enzymes LKB1 is the captain of a team of 14 different kinase members But since LKB1 was first identified as a major gene in lung cancer, it has been unclear for more than 15 years which kinase is specifically responsible for LKB1's cancer-suppressing function 2018, Shaw's lab solved the first step in the molecular puzzle, confirming that two of its 14 members (the main enzyme known to control metabolism and growth) are less important in blocking lung cancer in LKB1 than most scientists think This makes 12 members of kinases a potentially important molecule, but current studies know little about these enzymes declassify 12 enzymes " it's like a cancer detective case We suspect that one of these 12 kinases may be the key to LKB1's tumor suppression, but we're not sure which one In to clarify the problem, the team used CRISPR technology combined genetic analysis to inactivate each suspected kinase, inactivate one at a time, and then synthesize it The researchers looked at non-small cell lung cancer cell culture and non-small cell lung cancer mouse models, how this inactivation affects tumor growth and development eventually researchers discovered two types of kinases: one called SIK1, which was most effective at preventing tumor formation Tumor growth increases after SIK1 inactivation, and when a related kinase SIK3 is also inactivated, the tumor grows more rapidly double-feed "MVP" that is, a total of 14 kinases, SIK1 and SIK3 are the dual "MVP" of these The researchers further found that SIK1 and SIK3 had specific inhibitory effects on the inflammatory response of lung cancer cells Therefore, when LKB1 or SIK1 and SIK3 mutate in tumors, it promotes increased inflammation, which in turn promotes tumor growth related to this, Marc Montminy, a professor at Salk Labs, recently published a paper with Shaw that identified the metabolic switches of SIK1 and SIK3 "passing the baton", revealing three steps for the LKB1 start-up relay race conclusion ", by addressing lung cancer from different perspectives, we have now identified a direct way to support the development of many patients We've been working on this project since I started the experiment in 2006, so in this very clear lung cancer group, inflammation is the driving force behind tumor formation, which is an incredible and amazing discovery The findings highlight the nature of scientific research - persistence and focus, because sometimes it can take more than 10 years to get an answer," Shaw said next step, the researchers plan to further study how these kinase-driven inflammatory switches trigger lung tumor growth in non-small cell lung cancer References: the CREB coactivator CRTC2 promotes oncogenesis in LKB1-mutant non-small cell lung cancer s2.
