{"id":23537,"date":"2019-07-26T09:20:23","date_gmt":"2019-07-26T16:20:23","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&#038;p=23537"},"modified":"2024-01-30T14:53:29","modified_gmt":"2024-01-30T22:53:29","slug":"two-therapeutic-targets-identified-for-deadly-lung-cancer","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/zh\/news-release\/two-therapeutic-targets-identified-for-deadly-lung-cancer\/","title":{"rendered":"Two therapeutic targets identified for deadly lung cancer"},"content":{"rendered":"<p>LA JOLLA\u2014The vast majority of deadly lung cancer cases (85 percent) are termed non-small-cell lung carcinomas (NSCLCs), which often contain a mutated gene called LKB1. Salk Institute researchers have now discovered precisely why inactive LKB1 results in cancer development. The surprising results, published in the online version of <a href=\"http:\/\/cancerdiscovery.aacrjournals.org\/content\/early\/2019\/07\/26\/2159-8290.CD-18-1261\" target=\"_blank\" rel=\"noopener\"><em>Cancer Discovery<\/em><\/a> on July 26, 2019, highlight how LBK1 communicates with two enzymes that suppress inflammation in addition to cell growth, to block tumor growth. The findings could lead to new therapies for NSCLC, and you can see news coverage of the story <a href=\"https:\/\/www.youtube.com\/watch?v=5vg8P3QzT7Q\">here<\/a>.<\/p>\n<div class=\"row\" style=\"\"><div class=\"col-md-12 col-md-push-0\"><div class=\"video-anchor\" id=\"video-c3CNF7vi5MM\"><\/div><div class=\"embed-responsive embed-responsive-16by9\"> <iframe class=\"embed-responsive-item\" src=\"\/\/www.youtube.com\/embed\/c3CNF7vi5MM?rel=0\" webkitallowfullscreen mozallowfullscreen allowfullscreen><\/iframe><\/div><!-- .embed-responsive --><\/div><!-- .col-md-*size --><\/div><!-- .\/row -->\n<p>\u201cFor the first time, we\u2019ve found specific direct targets for LKB1 that prevent lung cancer and discovered\u2014very unexpectedly\u2014that inflammation plays a role in this tumor growth,\u201d says Professor <a href=\"https:\/\/www.salk.edu\/zh\/scientist\/reuben-shaw\/\">\u9c81\u672c-\u8096<\/a>, director of the Salk Cancer Center and senior author of the paper. \u201cWith this knowledge we can hopefully develop new treatments for this large fraction of lung cancer patients.\u201d<\/p>\n<figure id=\"attachment_23541\"  class=\"wp-caption alignright\"><img loading=\"lazy\" decoding=\"async\" width=\"458\" height=\"301\" class=\"img-responsive wp-image-23541 size-col-md-5\" src=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-458x301.jpg\" alt=\"From left: Reuben Shaw and Pablo Hollstein\" srcset=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-458x301.jpg 458w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-300x197.jpg 300w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-768x505.jpg 768w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-1024x674.jpg 1024w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-147x97.jpg 147w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-585x385.jpg 585w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-553x364.jpg 553w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-750x494.jpg 750w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-767x505.jpg 767w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-945x622.jpg 945w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-1250x823.jpg 1250w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500-400x263.jpg 400w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500.jpg 1500w\" sizes=\"auto, (max-width: 458px) 100vw, 458px\" \/><figcaption class=\"wp-caption-text\">From left: Reuben Shaw and Pablo Hollstein<\/p>\n<p><a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/PR_Shaw_Hollstein-1500.jpg\">Click here<\/a> for a high-resolution image.<\/p>\n<p>Credit: Salk Institute<\/figcaption><\/figure>\n<p>When functioning normally, LKB1 acts as a tumor suppressor, actively preventing cancer from forming in the first place. Scientists knew that the LKB1 gene worked like the captain of a relay team, passing cellular signals, like a baton, to enzymes called kinases, that then passed the signal to other enzymes in a chain reaction. LKB1 acts as the captain of a team consisting of 14 different kinase teammates. But which of these kinases is specifically responsible for carrying on LKB1\u2019s tumor suppressive function has been unclear for the more than 15 years since LKB1 was first identified as a major gene disrupted in lung cancer. In <a href=\"https:\/\/www.salk.edu\/zh\/news-release\/genetic-whodunnit-for-cancer-gene-solved\/\">2018<\/a>, the Shaw lab solved the first step of this molecular whodunnit by showing that 2 of the 14 teammates (the main enzymes known to control metabolism and growth) were surprisingly not as important to LKB1\u2019s effects to block lung cancer as most scientists had assumed. That left 12 of their kinase teammates as potentially important, but almost nothing was known about them.<\/p>\n<p>\u201cThis was like a cancer detective case. We suspected that one of these 12 kinases was likely the key to the tumor suppressing effects of LKB1, but we were not sure which one,\u201d says Pablo Hollstein, first author on the paper and a postdoctoral fellow at Salk.<\/p>\n<p>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 the inactivations affected tumor growth and development in both cell cultures of NSCLC cells and in a genetic NSCLC mouse model. The experiments pointed the researchers to two kinases: one called SIK1 had the strongest effect in stopping tumors from forming. When SIK1 was inactivated, tumor growth increased; and when a related kinase, SIK3, was also inactivated, the tumors grew even more aggressively.<\/p>\n<figure id=\"attachment_23544\"  class=\"wp-caption alignleft\"><a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500.jpg\"><img loading=\"lazy\" decoding=\"async\" width=\"458\" height=\"438\" class=\"img-responsive wp-image-23544 size-col-md-5\" src=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-458x438.jpg\" alt=\"\" srcset=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-458x438.jpg 458w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-300x287.jpg 300w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-768x735.jpg 768w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-1024x980.jpg 1024w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-147x141.jpg 147w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-585x560.jpg 585w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-553x529.jpg 553w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-750x718.jpg 750w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-767x734.jpg 767w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-945x905.jpg 945w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-1250x1197.jpg 1250w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500-400x383.jpg 400w, https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500.jpg 1500w\" sizes=\"auto, (max-width: 458px) 100vw, 458px\" \/><\/a><figcaption class=\"wp-caption-text\">Image of lung cancer shows normal lung (light purple) and tumors (dark purple). Inactivation of SIK1 and SIK3 leads to tumor growth and inflammation, revealing for the first time that SIK kinases mediate key functions of LKB1 in preventing lung cancer.<\/p>\n<p><a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2019\/07\/Image-Hollstein-et-al-Salk-PR_Caption-1500.jpg\">Click here<\/a> for a high-resolution image.<\/p>\n<p>Credit: Salk Institute<\/figcaption><\/figure>\n<p>\u201cDiscovering 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,\u201d says Shaw.<\/p>\n<p>LKB1 is also known to play a role in suppressing inflammation in cells generally, so the researchers were intrigued to discover that SIK1 and SIK3 were specifically inhibiting the cellular inflammation response in lung cancer cells. Thus, when LKB1 or SIK1 and SIK3 become mutated in tumors, inflammation is increased, driving tumor growth.<\/p>\n<p>In a related vein, Salk Professor Marc Montminy recently published a <a href=\"https:\/\/www.salk.edu\/zh\/news-release\/unlocking-therapies-for-hard-to-treat-lung-cancers\/\">paper<\/a> along with Shaw, identifying metabolic switches to which SIK1 and SIK3 \u201cpass the baton,\u201d revealing three steps of the relay started by LKB1.<\/p>\n<p>\u201cBy 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,\u201d says Shaw, who holds the William R. Brody Chair. \u201cWe have been working on this project since I started my lab in 2006, so it is incredibly rewarding and astonishing to find that inflammation is a driving force in tumor formation in this very clearly defined set of lung cancers. 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.\u201d<\/p>\n<p>Next, the researchers plan to further investigate how these kinase-driven switches in inflammation trigger lung tumor growth in NSCLC.<\/p>\n<p>Other authors included Lillian J. Eichner, Sonja N. Brun, Anwesh Kamireddy, Robert U. Svensson, Liliana I.<\/p>\n<p>Vera, Debbie S. Ross, T.J. Rymoff, Amanda Hutchins, Hector M. Galvez, April E. Williams, Maxim N.<\/p>\n<p>Shokhirev of Salk, along with Robert A. Screaton of the University of Toronto and Rebecca Berdeaux of the University of Texas.<\/p>\n<p>The work was funded by the National Institutes of Health (R35CA220538 and P01CA120964), the Samuel Waxman Cancer Research Foundation, The Leona M. and Harry B. Helmsley Charitable Trust (grant #2012-PG-MED002) and the American Cancer Society (ACS#124183-PF-13-023-01-CSM and PF-15-037-01-DMC).<\/p>","protected":false},"featured_media":23544,"template":"","faculty":[45],"disease-research":[46,164],"class_list":["post-23537","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-reuben-shaw","disease-research-cancer-biology","disease-research-lung-cancer"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Two therapeutic targets identified for deadly lung cancer - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/zh\/news-release\/two-therapeutic-targets-identified-for-deadly-lung-cancer\/\" \/>\n<meta property=\"og:locale\" content=\"zh_CN\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Two therapeutic targets identified for deadly lung cancer - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014The vast majority of deadly lung cancer cases (85 percent) are termed non-small-cell lung carcinomas (NSCLCs), which often contain a mutated gene called LKB1. 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