{"entity":{"id":"paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022","kind":"paper","name":"Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status","aka":[],"tldr":"Two genes long blamed for immunotherapy failure in lung cancer turn out to matter only when the tumour also has a mutated KRAS gene. In tumours without it, the same mutations made no difference at all.","summary":"Clinicopathological and genomic data were collected from patients with advanced lung adenocarcinoma at two multi-institutional cohorts, and outcomes on PD-(L)1 inhibition were analysed by KRAS, STK11 and KEAP1 mutation status. In the combined cohort of 1,261 patients, KRAS mutations were detected in 536 cases, 42.5%, deleterious STK11 mutations in 260 of 1,261, 20.6%, and deleterious KEAP1 mutations in 231 of 1,202 assessable cases, 19.2%. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free survival (hazard ratios 2.04 and 2.05) and overall survival (2.09 and 2.24) on immunotherapy uniquely among KRAS-mutant but not KRAS wild-type adenocarcinomas. Gene expression and immune cell enrichment analyses showed that STK11 or KEAP1 mutation produced distinct immunophenotypes only in KRAS-mutant tumours.","asOf":"2026-09-25","links":[{"label":"Ricciuti et al., J Thorac Oncol 2022: STK11 and KEAP1 mutations and PD-(L)1 inhibition in 1,261 lung adenocarcinomas, by KRAS status","url":"https://doi.org/10.1016/j.jtho.2021.10.013"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34740862/"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["checkpoint-inhibitor","cgp"],"targets":["stk11","keap1","kras","pdl1","pd1"],"drugs":[],"companies":[],"institutions":["dana-farber","mgh","mskcc","md-anderson"],"pathways":["t-cell-exhaustion","keap1-nrf2","pd1-checkpoint"],"terms":["stk11-keap1","kras-mutation-subtypes","cold-vs-hot"],"trials":[],"people":["ferdinandos-skoulidis"],"bottlenecks":[],"keyPapers":[],"journals":["journal-of-thoracic-oncology"],"dependsOn":[],"notes":[],"journal":"Journal of Thoracic Oncology","year":2022,"doi":"10.1016/j.jtho.2021.10.013","pmid":"34740862","authors":"Ricciuti B, Arbour KC, Lin JJ, et al.","paperType":"observational","findings":["STK11 mutation in 20.6% and KEAP1 mutation in 19.2% of lung adenocarcinomas across two cohorts.","Both predicted worse progression-free and overall survival on PD-(L)1 blockade only in KRAS-mutant tumours.","In KRAS wild-type tumours neither mutation affected outcome.","The immune phenotype differences were also confined to KRAS-mutant disease."],"whatItMeans":"It corrected a widely repeated simplification. An STK11 or KEAP1 mutation is not by itself a reason to expect immunotherapy to fail; it is a reason to expect it in a KRAS-mutant tumour, which is how the result should be read on a report.","caveats":["Retrospective across two cohorts with different treatment practices.","Deleterious mutation calling depends on the annotation pipeline.","Patients received several different regimens."],"changedPractice":false,"participants":1261},"route":"/key-papers/paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022/","neighbours":{"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"target":[{"id":"keap1","kind":"target","name":"KEAP1","route":"/targets/keap1/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"},{"id":"stk11","kind":"target","name":"STK11","route":"/targets/stk11/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"mgh","kind":"institution","name":"Massachusetts General Hospital Cancer Center","route":"/institutions/mgh/"},{"id":"md-anderson","kind":"institution","name":"MD Anderson Cancer Center","route":"/institutions/md-anderson/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"keap1-nrf2","kind":"pathway","name":"KEAP1-NRF2 antioxidant pathway","route":"/pathways/keap1-nrf2/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"t-cell-exhaustion","kind":"pathway","name":"T-cell exhaustion","route":"/pathways/t-cell-exhaustion/"}],"term":[{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"kras-mutation-subtypes","kind":"term","name":"KRAS mutation subtypes (G12C, G12D, G12V)","route":"/terms/kras-mutation-subtypes/"},{"id":"stk11-keap1","kind":"term","name":"STK11 / KEAP1 co-mutations","route":"/terms/stk11-keap1/"}],"person":[{"id":"ferdinandos-skoulidis","kind":"person","name":"Ferdinandos Skoulidis","route":"/people/ferdinandos-skoulidis/"}],"journal":[{"id":"journal-of-thoracic-oncology","kind":"journal","name":"Journal of Thoracic Oncology","route":"/journals/journal-of-thoracic-oncology/"}],"biomarker":[{"id":"stk11-keap1-loss","kind":"biomarker","name":"STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma","route":"/biomarkers/stk11-keap1-loss/"}]}}