Impact of RAS-MAPK Pathway Genetic Alterations on Radiotherapy Response in Metastatic Lung Adenocarcinoma
Gustav Y Cederquist1, Erik S Anderson1, Eric Lis2
1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.
JCO Precision Oncology
|December 5, 2025
Summary
Driver gene alterations in the RAS-MAPK pathway, such as NF1 and BRAF mutations, are linked to higher rates of local failure in non-small cell lung cancer (NSCLC) spine metastases treated with radiotherapy. These findings suggest potential biomarkers for personalizing radiation therapy.
Area of Science:
- Oncology
- Genetics
- Radiation Oncology
Background:
- Metastatic non-small cell lung cancer (NSCLC) often requires radiotherapy (RT) for spine metastases.
- Predicting treatment response in NSCLC patients is crucial for optimizing outcomes.
- Driver gene alterations are key in NSCLC pathogenesis and treatment resistance.
Purpose of the Study:
- To investigate the association between driver gene alterations in NSCLC spine metastases and local tumor control after RT.
- To identify specific genetic mutations that may predict radioresistance or radiosensitivity.
Main Methods:
- Retrospective analysis of 181 NSCLC patients who received RT for spine metastases and underwent genetic profiling.
- Statistical analysis of driver gene mutations and local failure incidence, including competing risk analysis.
- In vitro validation using CRISPR-engineered NSCLC cell lines to assess radioresistance.
Main Results:
- Patients with NF1 or BRAF driver alterations showed significantly higher 3-year local failure rates after RT.
- NF1 loss-of-function mutations conferred radioresistance in vitro.
- RAS-MAPK pathway driver alterations were associated with 53% of local failures and increased risk, even with stereotactic body RT.
Conclusions:
- Driver alterations within the RAS-MAPK signaling pathway contribute to radioresistance in metastatic NSCLC spine metastases.
- These genetic alterations can potentially serve as biomarkers for tailoring RT strategies.
- Targeting RAS-MAPK pathway alterations may enhance radiosensitivity and improve treatment efficacy.
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