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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.
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).
In plain words · STK11 is a protein kinase, an enzyme that switches other proteins on by adding phosphate groups. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor, a biomarker and a DNA repair gene, and clinical evidence ties its variants to diagnosis, prognosis or drug response.
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.
Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.
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.
“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”
Ricciuti et al., Journal of Thoracic Oncology 2022No approval uses this readout as a threshold. It is defined by Skoulidis et al., Cancer Discovery 2018: STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma.
It is the positive half of the tumour mutational burden story and it applies only to single-agent immunotherapy, which is the setting fewest patients are treated in.
This is the result that ended tumour mutational burden as a practical selector in lung cancer: in the regimen most patients receive, it selects nobody, and neither do the co-mutations most often quoted as reasons to withhold immunotherapy.
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.
One of the most cited trial reports Europe PMC returns for KRAS in Non-small-cell lung cancer, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.
It separated the prognostic co-mutation, KEAP1, from the predictive one, STK11, in a disease where the two are often quoted together, and it is the reason KEAP1 status is worth reading off a report even though no treatment depends on it.
Shares STK11 / KEAP1 co-mutations, KEAP1-NRF2 antioxidant pathway, KEAP1, STK11.
Shares Drug resistance (primary and acquired), Comprehensive genomic profiling, Non-small-cell lung cancer and the tag biomarker.
Shares Drug resistance (primary and acquired), Comprehensive genomic profiling, Non-small-cell lung cancer and the tag biomarker.
Shares 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, Associations of tissue tumour mutational burden and mutational status with clinical outcomes in KEYNOTE-042, Non-small-cell lung cancer and the tag biomarker.
Shares STK11 / KEAP1 co-mutations, KEAP1, STK11, T-cell exhaustion.
Shares PD-L1 TPS (tumour proportion score), Non-small-cell lung cancer and the tag biomarker.
Shares PD-L1 TPS (tumour proportion score), Non-small-cell lung cancer and the tag biomarker.
Shares KRAS G12C, Non-small-cell lung cancer and the tag biomarker.