{"entity":{"id":"stk11-keap1-loss","kind":"biomarker","name":"STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma","aka":["STK11 mutation","LKB1 loss","KEAP1 mutation","STK11/KEAP1 co-mutation","KL subtype"],"tldr":"Two genes that, when broken in a lung cancer that also has a faulty KRAS gene, predict that immunotherapy will work much less well. In a lung cancer with a normal KRAS gene the same faults appear to make no difference.","summary":"STK11 (LKB1) and KEAP1 are among the most frequently inactivated genes in lung adenocarcinoma, at 13 to 18% and 11 to 18% by cohort, rising to 22.1% each among patients selected for PD-(L)1 blockade (cBioPortal). STK11 loss makes a tumour immune-poor, with low PD-L1 and few infiltrating lymphocytes, and was first tied to PD-1 inhibitor resistance in KRAS-mutant disease (Skoulidis 2018); KEAP1 loss frees NRF2 and switches on an antioxidant programme, and was the strongest independent predictor of short survival among 330 KRAS-mutant patients (hazard ratio 1.96, and 3.54 from the start of immunotherapy) (Arbour 2018). The dependence on KRAS status is the part most often forgotten: across 1,261 patients in two cohorts, STK11 and KEAP1 mutations predicted worse progression-free survival (hazard ratios 2.04 and 2.05) and overall survival (2.09 and 2.24) on PD-(L)1 blockade only in KRAS-mutant tumours, with no effect in KRAS wild-type disease, and the immune phenotype differences were similarly confined (Ricciuti 2022). In the randomised setting the picture is weaker still: neither gene changed the benefit of pembrolizumab monotherapy in KEYNOTE-042 nor of pembrolizumab with chemotherapy in KEYNOTE-189 and KEYNOTE-407 (Mok 2023, Garassino 2023).","asOf":"2026-09-25","links":[{"label":"Skoulidis et al., Cancer Discov 2018: STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma","url":"https://doi.org/10.1158/2159-8290.CD-18-0099"},{"label":"Arbour et al., Clin Cancer Res 2018: co-occurring alterations and outcomes in 330 KRAS-mutant lung cancers","url":"https://doi.org/10.1158/1078-0432.CCR-17-1841"},{"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":"cBioPortal study nsclc_pd1_msk_2018 (MSK, J Clin Oncol 2018; 240 non-small-cell lung cancers profiled before PD-(L)1 blockade)","url":"https://www.cbioportal.org/study/summary?id=nsclc_pd1_msk_2018"}],"tags":["biomarker","immunotherapy"],"related":["kras-g12c","kras-g12d","pd-l1-tps"],"cancers":["nsclc"],"sections":[],"technologies":["cgp","checkpoint-inhibitor"],"targets":["stk11","keap1","kras"],"drugs":[],"companies":[],"institutions":[],"pathways":["t-cell-exhaustion","keap1-nrf2","ras-mapk","pd1-checkpoint"],"terms":["stk11-keap1","kras-mutation-subtypes","cold-vs-hot","resistance"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-kras-nsclc-cancer-discov-2018","paper-arbour-kras-co-mutation-outcomes-ccr-2018","paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022","paper-keynote-042-tmb-mutations-ann-oncol-2023","paper-keynote-189-407-tmb-jtocrr-2023"],"journals":[],"dependsOn":[],"notes":[],"target":"stk11","measurement":"sequencing-variant","scoringRule":{"text":"A deleterious (truncating, splice-site or known damaging missense) mutation in STK11 or KEAP1 on tumour sequencing, interpreted only together with KRAS status, since the association with immunotherapy outcome is confined to KRAS-mutant tumours.","quote":"STK11 and KEAP1 mutations were associated with significantly worse progression-free and overall survival to immunotherapy uniquely among KRAS-mutant but not KRAS wild-type lung adenocarcinomas","source":"https://doi.org/10.1016/j.jtho.2021.10.013","sourceLabel":"Ricciuti et al., Journal of Thoracic Oncology 2022"},"thresholds":[],"definedBy":{"label":"Skoulidis et al., Cancer Discovery 2018: STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma","url":"https://doi.org/10.1158/2159-8290.CD-18-0099"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This result is a prediction about how well immunotherapy is likely to work, not a rule about what can be given. It is used alongside the PD-L1 result and the rest of the genetic report when a treatment plan is discussed, and it matters mainly when the cancer also carries a KRAS change."},"route":"/biomarkers/stk11-keap1-loss/","neighbours":{"biomarker":[{"id":"kras-g12c","kind":"biomarker","name":"KRAS G12C","route":"/biomarkers/kras-g12c/"},{"id":"kras-g12d","kind":"biomarker","name":"KRAS G12D (and other non-G12C KRAS mutations)","route":"/biomarkers/kras-g12d/"},{"id":"pd-l1-tps","kind":"biomarker","name":"PD-L1 TPS (tumour proportion score)","route":"/biomarkers/pd-l1-tps/"}],"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":"stk11","kind":"target","name":"STK11","route":"/targets/stk11/"}],"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":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"t-cell-exhaustion","kind":"pathway","name":"T-cell exhaustion","route":"/pathways/t-cell-exhaustion/"}],"term":[{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"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/"}],"paper":[{"id":"paper-keynote-042-tmb-mutations-ann-oncol-2023","kind":"paper","name":"Associations of tissue tumour mutational burden and mutational status with clinical outcomes in KEYNOTE-042","route":"/key-papers/paper-keynote-042-tmb-mutations-ann-oncol-2023/"},{"id":"paper-keynote-189-407-tmb-jtocrr-2023","kind":"paper","name":"Associations of tissue tumour mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic non-small-cell lung cancer","route":"/key-papers/paper-keynote-189-407-tmb-jtocrr-2023/"},{"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","route":"/key-papers/paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022/"},{"id":"paper-arbour-kras-co-mutation-outcomes-ccr-2018","kind":"paper","name":"Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer","route":"/key-papers/paper-arbour-kras-co-mutation-outcomes-ccr-2018/"},{"id":"paper-kras-nsclc-cancer-discov-2018","kind":"paper","name":"STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma","route":"/key-papers/paper-kras-nsclc-cancer-discov-2018/"}]}}