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Updated: Jan 9, 2026

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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
PubMed
Abstract

Insights

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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