{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:00:08Z","timestamp":1792789208703,"version":"4.5.0"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2020,6,13]],"date-time":"2020-06-13T00:00:00Z","timestamp":1592006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title\/>\n                  <jats:p>STK11 was first recognized as a tumor suppressor gene in the late 1990s based on linkage analysis of patients with Peutz-Jeghers syndrome. STK11 encodes LKB1, an intracellular serine-threonine kinase involved in cellular metabolism, cell polarization, regulation of apoptosis, and DNA damage response. Recurrent somatic loss-of-function mutations occur in multiple cancer types, most notably in 13% of lung adenocarcinomas. Recent reports indicate that KRAS-mutant non-small cell lung cancers harboring co-mutations in STK11 do not respond to PD-1 axis inhibitors. We present three patients with STK11-mutated tumors and discuss the proposed mechanisms by which germline and somatic alterations in STK11 promote carcinogenesis, potential approaches for therapeutic targeting, and the new data on resistance to immune checkpoint inhibitors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:p>STK11 is a tumor suppressor gene, and loss-of-function mutations are oncogenic, due at least in part to loss of AMPK regulation of mTOR and HIF-1-\u03b1. Clinical trials are under way, offering hope to patients whose STK11-mutated tumors are refractory and\/or have progressed on chemotherapeutic regimens. Whether gastrointestinal cancers with STK11 loss of function will show the same outcome and potential refractoriness to immune therapy that were reported for lung cancer is unknown. However, physicians managing such patients should consider the experience in lung cancer, particularly outside the context of a clinical trial. In the CheckMate-057 trial lung tumors harboring co-mutations in KRAS and STK11 had an inferior response to PD-1 axis inhibitors. Coupled with the observation that STK11-mutated tumors were found to have a cold immune microenvironment regardless of KRAS status, the conclusion could extend to KRAS wild-type tumors with STK11 mutation. Current data suggest that the use of PD-1 axis inhibitors may be ill advised in the presence of STK11 mutation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1634\/theoncologist.2019-0846","type":"journal-article","created":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T19:55:32Z","timestamp":1589313332000},"page":"733-737","source":"Crossref","is-referenced-by-count":55,"title":["Emerging Therapeutic Implications of <i>STK11<\/i> Mutation: Case Series"],"prefix":"10.1093","volume":"25","author":[{"given":"Bahar","family":"Laderian","sequence":"first","affiliation":[{"name":"Columbia University Irving Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabhjot","family":"Mundi","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center, New York, New York, USA"},{"name":"James. J. Peters Bronx VA Medical Center, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tito","family":"Fojo","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center, New York, New York, USA"},{"name":"James. J. Peters Bronx VA Medical Center, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"E. Bates","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center, New York, New York, USA"},{"name":"James. J. Peters Bronx VA Medical Center, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,6,13]]},"reference":[{"key":"2021122510521932700_onco13364-bib-0001","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1126\/science.1178377","article-title":"Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation","volume":"326","author":"Zeqiraj","year":"2009","journal-title":"Science"},{"key":"2021122510521932700_onco13364-bib-0002","doi-asserted-by":"crossref","first-page":"427","DOI":"10.5732\/cjc.013.10086","article-title":"Dysregulation of mTOR activity through LKB1 inactivation","volume":"32","author":"Zhou","year":"2013","journal-title":"Chin J Cancer"},{"key":"2021122510521932700_onco13364-bib-0003","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.1242\/jcs.051011","article-title":"mTOR signaling at a glance","volume":"122","author":"Laplante","year":"2009","journal-title":"J Cell Sci"},{"key":"2021122510521932700_onco13364-bib-0004","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1073\/pnas.1312570111","article-title":"Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1alpha","volume":"111","author":"Faubert","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021122510521932700_onco13364-bib-0005","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.apsb.2015.05.007","article-title":"HIF-1alpha pathway: Role, regulation and intervention for cancer therapy","volume":"5","author":"Masoud","year":"2015","journal-title":"Acta Pharm Sin B"},{"key":"2021122510521932700_onco13364-bib-0006","doi-asserted-by":"crossref","first-page":"32","DOI":"10.2174\/1389450114666140106095811","article-title":"Targeting the LKB1 tumor suppressor","volume":"15","author":"Zhao","year":"2014","journal-title":"Curr Drug Targets"},{"key":"2021122510521932700_onco13364-bib-0007","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1004721","article-title":"A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1\/CIP1) degradation","volume":"10","author":"Esteve-Puig","year":"2014","journal-title":"PLoS Genet"},{"key":"2021122510521932700_onco13364-bib-0008","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.yasu.2010.05.011","article-title":"Update on familial pancreatic cancer","volume":"44","author":"Hruban","year":"2010","journal-title":"Adv Surg"},{"key":"2021122510521932700_onco13364-bib-0009","doi-asserted-by":"crossref","first-page":"3784","DOI":"10.1038\/onc.2011.98","article-title":"Frequent homozygous deletion of the LKB1\/STK11 gene in non-small cell lung cancer","volume":"30","author":"Gill","year":"2011","journal-title":"Oncogene"},{"key":"2021122510521932700_onco13364-bib-0010","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2018.03.035","article-title":"Oncogenic signaling pathways in The Cancer Genome Atlas","volume":"173","author":"Sanchez-Vega","year":"2018","journal-title":"Cell"},{"key":"2021122510521932700_onco13364-bib-0011","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov"},{"key":"2021122510521932700_onco13364-bib-0012","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","author":"Gao","year":"2013","journal-title":"Sci Signal"},{"key":"2021122510521932700_onco13364-bib-0013","article-title":"OncoKB: A precision oncology knowledge base","volume":"2017","author":"Chakravarty","year":"2017","journal-title":"JCO Precis Oncol"},{"key":"2021122510521932700_onco13364-bib-0014","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1200\/JCO.2017.75.3384","article-title":"Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing","volume":"36","author":"Rizvi","year":"2018","journal-title":"J Clin Oncol"},{"key":"2021122510521932700_onco13364-bib-0015","first-page":"3659","article-title":"Inactivation of LKB1\/STK11 is a common event in adenocarcinomas of the lung","volume":"62","author":"Sanchez-Cespedes","year":"2002","journal-title":"Cancer Res"},{"key":"2021122510521932700_onco13364-bib-0016","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/bjc.2015.261","article-title":"Targeting LKB1 in cancer - 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