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In Situ RAS:RAF Binding Correlates with Response to KRASG12C Inhibitors in KRASG12C-Mutant Non-Small Cell Lung

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Evaluating RAS-RAF interactions using proximity ligation assays (PLA) can predict non-small cell lung cancer (NSCLC) response to KRASG12C inhibitors (KRASG12Ci). This method helps identify patients likely to benefit from targeted therapy.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Biomarker Discovery

Background:

  • Therapeutic efficacy of KRASG12C inhibitors (KRASG12Ci) in KRASG12C-mutant non-small cell lung cancer (NSCLC) is variable.
  • The precise RAS signaling activation status in these tumors and its impact on treatment response remain unclear.

Purpose of the Study:

  • To investigate if RAS-RAF interactions can serve as a predictive biomarker for KRASG12Ci response in NSCLC.
  • To develop and validate a method for measuring in situ RAS-RAF interactions.

Main Methods:

  • Developed a proximity ligation assay (PLA) to detect panRAS-CRAF interactions in cancer samples.
  • Correlated PLA signals with RAS-GTP levels and phosphorylated ERK (pERK) as indicators of RAS pathway activity.
  • Assessed EGFR-Grb2 interactions as a control for pathway-specific activity.

Main Results:

  • The panRAS-CRAF PLA assay accurately reflected active RAS signaling, correlating with RAS-GTP and pERK levels.
  • Elevated RAS-RAF PLA signals were associated with increased sensitivity to KRASG12Ci in cell lines, xenografts, and patient samples.
  • EGFR activity did not correlate with response to KRASG12Ci.

Conclusions:

  • In situ RAS-RAF interactions are a potential predictive biomarker for KRASG12Ci therapy in NSCLC.
  • The developed PLA method is a valuable tool for assessing RAS activity and guiding treatment decisions for NSCLC patients.