STK11 & KEAP1

STK11

  • Serine/threonine kinase 11—tumor suppressor (STK11; also known as LKB1)
  • Gene location: chromosome 19p13.3

KEAP1

  • Kelch-like ECH-associated protein 1—negative regulator of NRF2 (KEAP1)
  • Gene location: chromosome 19p13.2

Biology

  • STK11 (LKB1) encodes a serine/threonine kinase that regulates cellular energy metabolism, polarity, and growth through activation of the AMPK pathway.1,2
  • KEAP1 encodes a cytoplasmic inhibitor of the NRF2 transcription factor, which governs oxidative stress responses.1,3
  • Loss of STK11 function leads to metabolic reprogramming and unchecked cell growth, whereas mutations in KEAP1 result in constitutive NRF2 activation that promotes antioxidant activity, resistance to therapy, and tumor survival.1-3
  • In NSCLC, especially lung adenocarcinoma, co-mutations in STK11 and KEAP1 are frequent; they contribute to aggressive tumor biology, immune evasion, and poor therapeutic responses.1,4

Etiology & Epidemiology

  • STK11 is mutated in approximately 15% to 30% of NSCLC cases, particularly those with adenocarcinoma histology; KEAP1 mutations occur in 17% to 23% of cases.1,4,5
  • These mutations are more common in smokers; they rarely overlap with EGFR or ALK alterations.1,4
  • Co-mutations of STK11 and KEAP1 frequently occur, often alongside KRAS mutations, forming distinct molecular subtypes characterized by aggressive tumor biology, metabolic reprogramming, immune evasion, high tumor mutational burden, and poor response to therapies.1,2,4,6

Testing

When to Test:

  • Genetic testing for STK11 and KEAP1 is recommended at the time of diagnosis for advanced NSCLC to assist in prognosis and guide trial enrollment.6

Available Testing Methods:

  • Next-generation sequencing is used to detect STK11 and KEAP1 alterations in tumor tissue or circulating tumor DNA.1,6
  • Comprehensive genomic profiling panels often include STK11 and KEAP1 due to their clinical and biological significance.6

Guideline Recommendations

  • NCCN guidelines (version 7.2025) recommend molecular testing for key mutations, including STK11 and KEAP1, in all patients with advanced NSCLC as part of broader panels.6
  • There are currently no FDA-approved therapies that directly target STK11 or KEAP1 alterations. However, testing for these mutations is important for prognostic assessment and to inform clinical trial eligibility, particularly concerning immunotherapy resistance and poor response to standard treatments.6

Targeted Therapy

Approved Therapies:

  • There are currently no approved therapies directly targeting STK11 or KEAP1. Current strategies focus on therapy escalation based on the presence of these alterations.6
  • Ongoing clinical trials are evaluating combination regimens involving ICIs, chemotherapy, and novel metabolic or NRF2-pathway inhibitors in patients with STK11/KEAP1 mutations.1,7
  • STK11/KEAP1-mutant NSCLC may benefit from future targeted approaches addressing metabolic vulnerabilities and oxidative stress dependencies.7

Therapeutic Implications:

  • Decreased Response With Standard Therapies:
    • STK11 or KEAP1 mutations are associated with poor outcomes following use of immune checkpoint inhibitors (ICIs), chemotherapy, and targeted therapies.1,3
    • In particular, STK11-mutated tumors display cold immune profiles that are characterized by low PD-L1 expression, low CD8+ T-cell infiltration, and reduced interferon signaling that contribute to resistance to ICIs.1,5
    • KEAP1-mutated tumors, although often having a high tumor mutational burden, paradoxically exhibit resistance to both ICIs and chemotherapy due to enhanced oxidative stress protection and metabolic rewiring.3,5
  • Biological Mechanism of Resistance:
    • STK11 loss disrupts AMPK signaling, promoting anabolic metabolism and limiting immune recognition through a cold tumor microenvironment.1,2
    • KEAP1 loss leads to sustained NRF2 activation, resulting in detoxification of reactive oxygen species, suppression of pro-inflammatory signaling, and evasion of therapy-induced cytotoxicity.3,5
    • Together, these mutations enhance cell survival, reduce immune-mediated killing, and lead to poor response to ICIs and standard therapies.5

Investigational Therapies:

  • TRITON8
    • ClinicalTrials.gov: NCT06008093
    • Study design: Phase 3b, randomized, open-label trial comparing durvalumab plus tremelimumab plus chemotherapy versus pembrolizumab plus chemotherapy in treatment‑naïve patients with metastatic, nonsquamous NSCLC with STK11, KEAP1, and/or KRAS mutations. This study includes biomarker‐defined enrollment; results will clarify whether dual checkpoint blockade overcomes resistance driven by these co‑mutations.

References

  1. Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. CancerDiscov . 2018;8(7):822-835. doi:10.1158/2159-8290.CD-18-0099
  2. Papillon-Cavanagh S, Doshi P, Dobrin R, Szustakowski J, Walsh AM. STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort. ESMO Open. 2020;5(2):e000706. doi:10.1136/esmoopen-2020-000706
  3. Di Federico A, De Giglio A, Parisi C, Gelsomino F. STK11/LKB1 and KEAP1 mutations in non-small cell lung cancer: prognostic rather than predictive? Eur J Cancer. 2021;157:108-113. doi:10.1016/j.ejca.2021.08.011
  4. Knetki-Wróblewska M, Wojas-Krawczyk K, Krawczyk P, Krzakowski M. Emerging insights into STK11, KEAP1 and KRAS mutations: implications for immunotherapy in patients with advanced non-small cell lung cancer. Transl Lung Cancer Res. 2024;13(12):3718-3730. doi:10.21037/tlcr-24-552
  5. Cordeiro de Lima VC, Corassa M, Saldanha E, et al. STK11 and KEAP1 mutations in non-small cell lung cancer patients: descriptive analysis and prognostic value among Hispanics (STRIKE registry-CLICaP). Lung Cancer. 2022;170:114-121. doi:10.1016/j.lungcan.2022.06.010‌
  6. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 7.2025. Accessed July 21, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  7. Shiller M, Johnson M, Auber R, Patel SP. Clinical perspectives on the value of testing for STK11 and KEAP1 mutations in advanced NSCLC. Front Oncol. 2024;14. doi:10.3389/fonc.2024.1459737
  8. A study to investigate the efficacy of durvalumab plus tremelimumab in combination with chemotherapy compared with pembrolizumab in combination with chemotherapy in metastatic NSCLC patients with non-squamous histology who have mutations and/​or co-mutations in STK11, KEAP1, or KRAS (TRITON). ClinicalTrials.gov. Updated July 20, 2025. Accessed July 22, 2025. https://clinicaltrials.gov/study/NCT06008093