# STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma

Source: https://onco.cc/biomarkers/stk11-keap1-loss/  
OnCo record `stk11-keap1-loss` (Biomarker). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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).

## Fields

- Kind: Biomarker
- Last checked: 2026-09-25
- Also known as: STK11 mutation; LKB1 loss; KEAP1 mutation; STK11/KEAP1 co-mutation; KL subtype
- Tags: biomarker; immunotherapy

## Sources

- Skoulidis et al., Cancer Discov 2018: STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma: https://doi.org/10.1158/2159-8290.CD-18-0099
- Arbour et al., Clin Cancer Res 2018: co-occurring alterations and outcomes in 330 KRAS-mutant lung cancers: https://doi.org/10.1158/1078-0432.CCR-17-1841
- Ricciuti et al., J Thorac Oncol 2022: STK11 and KEAP1 mutations and PD-(L)1 inhibition in 1,261 lung adenocarcinomas, by KRAS status: https://doi.org/10.1016/j.jtho.2021.10.013
- cBioPortal study nsclc_pd1_msk_2018 (MSK, J Clin Oncol 2018; 240 non-small-cell lung cancers profiled before PD-(L)1 blockade): https://www.cbioportal.org/study/summary?id=nsclc_pd1_msk_2018

## Connected records

- biomarkers: [KRAS G12C](https://onco.cc/biomarkers/kras-g12c/), [KRAS G12D (and other non-G12C KRAS mutations)](https://onco.cc/biomarkers/kras-g12d/), [PD-L1 TPS (tumour proportion score)](https://onco.cc/biomarkers/pd-l1-tps/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [KEAP1](https://onco.cc/targets/keap1/), [KRAS](https://onco.cc/targets/kras/), [STK11](https://onco.cc/targets/stk11/)
- pathways: [KEAP1-NRF2 antioxidant pathway](https://onco.cc/pathways/keap1-nrf2/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [T-cell exhaustion](https://onco.cc/pathways/t-cell-exhaustion/)
- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [KRAS mutation subtypes (G12C, G12D, G12V)](https://onco.cc/terms/kras-mutation-subtypes/), [STK11 / KEAP1 co-mutations](https://onco.cc/terms/stk11-keap1/)
- key papers: [Associations of tissue tumour mutational burden and mutational status with clinical outcomes in KEYNOTE-042](https://onco.cc/key-papers/paper-keynote-042-tmb-mutations-ann-oncol-2023/), [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](https://onco.cc/key-papers/paper-keynote-189-407-tmb-jtocrr-2023/), [Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status](https://onco.cc/key-papers/paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022/), [Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer](https://onco.cc/key-papers/paper-arbour-kras-co-mutation-outcomes-ccr-2018/), [STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma](https://onco.cc/key-papers/paper-kras-nsclc-cancer-discov-2018/)

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