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Two genes whose loss, often alongside a KRAS mutation, makes lung cancer 'cold' to immunotherapy and shortens survival on standard treatment. They are the reason two KRAS-mutant lung cancers can behave completely differently.
STK11 (LKB1) and KEAP1 are inactivated in about 15-20% of lung adenocarcinomas each. Tumours with these losses have low PD-L1, few infiltrating T cells and poor responses to PD-1 blockade and chemo-immunotherapy, and KEAP1 loss also blunts chemotherapy and radiotherapy through antioxidant (NRF2) activation. They are stratification factors and exclusion criteria in modern lung trials, and are targets of dedicated strategies: glutaminase inhibition for KEAP1, and adding CTLA-4 blockade (POSEIDON subgroup) for STK11. SMARCA4 loss is a third co-mutation with similar prognostic weight.
In plain words · KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.
Showing the target this term concerns: KRAS.
The glossary entry explains the word; the readout page carries the scoring rule, the thresholds approvals use, the companion diagnostics and the tests.
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.
It turned a frequently reported variant into an interpretable one: the class decides whether the stain will be negative, how poor the prognosis is, and whether immunotherapy is more rather than less likely to help.
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.
It made tumour mutational burden measurable in routine practice and, in the same stroke, showed it is a second axis alongside PD-L1 rather than a replacement for it.
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 is the honest accounting of precision oncology in the disease where it works best: broad sequencing changes treatment for about one patient in three, and the bottleneck is evidence rather than detection.
Shares Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities, Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status, STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma.
Shares The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer, Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies, Non-small-cell lung cancer.
Shares The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer, Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma, Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
Shares Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities, Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status, KRAS, Non-small-cell lung cancer.
Shares Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma, STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma, KRAS mutation subtypes (G12C, G12D, G12V).
Shares Associations of tissue tumour mutational burden and mutational status with clinical outcomes in KEYNOTE-042, Molecular determinants of response to anti-PD-1 and anti-PD-L1 blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing, STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma, PD-L1 expression testing (22C3, SP142, SP263).
Shares KEAP1, STK11, Non-small-cell lung cancer.
Shares KEAP1, STK11, Non-small-cell lung cancer.