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Updated: Oct 11, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Functional assessment of somatic STK11 variants identified in primary human non-small cell lung cancers
Liam L Donnelly1, Tyler C Hogan2, Sean M Lenahan1
1Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.
Abstract:
Serine/Threonine Kinase 11 (STK11) encodes an important tumor suppressor that is frequently mutated in lung adenocarcinoma. Clinical studies have shown that mutations in STK11 resulting in loss of function correlate with resistance to anti-PD-1 monoclonal antibody therapy in KRAS-driven non-small cell lung cancer (NSCLC), but the molecular mechanisms responsible remain unclear. Despite this uncertainty, STK11 functional status is emerging as a reliable biomarker for predicting non-response to anti-PD-1 therapy in NSCLC patients. The clinical utility of this biomarker ultimately depends upon accurate classification of STK11 variants. For nonsense variants occurring early in the STK11 coding region, this assessment is straightforward. However, rigorously demonstrating the functional impact of missense variants remains an unmet challenge. Here we present data characterizing four STK11 splice-site variants by analyzing tumor mRNA, and 28 STK11 missense variants using an in vitro kinase assay combined with a cell-based p53-dependent luciferase reporter assay. The variants we report were identified in primary human NSCLC biopsies in collaboration with the University of Vermont Genomic Medicine group. Additionally, we compare our experimental results with data from 22 in silico predictive algorithms. Our work highlights the power, utility and necessity of functional variant assessment and will aid STK11 variant curation, provide a platform to assess novel STK11 variants and help guide anti-PD-1 therapy utilization in KRAS-driven NSCLCs.
Insights
Assessing Serine/Threonine Kinase 11 (STK11) variants is crucial for predicting anti-PD-1 therapy response in lung cancer. Functional assays help classify STK11 variants, guiding treatment decisions for non-small cell lung cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Serine/Threonine Kinase 11 (STK11) is a key tumor suppressor frequently mutated in lung adenocarcinoma.
- Loss-of-function STK11 mutations are linked to resistance to anti-PD-1 immunotherapy in KRAS-driven non-small cell lung cancer (NSCLC).
- STK11 functional status is a potential biomarker for predicting anti-PD-1 therapy response in NSCLC.
Purpose of the Study:
- To functionally characterize STK11 variants identified in NSCLC patient biopsies.
- To evaluate the utility of in vitro and cell-based assays for assessing STK11 variant impact.
- To compare experimental findings with in silico predictive algorithms for variant classification.
Main Methods:
- Analysis of tumor mRNA to characterize four STK11 splice-site variants.
- In vitro kinase assays and cell-based p53-dependent luciferase reporter assays for 28 STK11 missense variants.
- Comparison of experimental data with 22 in silico predictive algorithms.
Main Results:
- Characterization of four STK11 splice-site variants and 28 missense variants.
- Demonstration of functional impacts of STK11 variants through biochemical and cell-based assays.
- Evaluation of the concordance between experimental results and in silico predictions.
Conclusions:
- Functional assessment is essential for accurate classification of STK11 variants.
- Developed assays can aid in STK11 variant curation and assessment of novel variants.
- This work supports the use of STK11 functional status to guide anti-PD-1 therapy in KRAS-driven NSCLC.
