Clinically Viable Gene Expression Assays with Potential for Predicting Benefit from MEK Inhibitors.

Area of Science:

• Molecular Oncology
• Biomarker Discovery
• Cancer Genomics

Background:

• The RAS/RAF/MEK/ERK (RAS-ERK) pathway is crucial in non-small cell lung cancer (NSCLC) pathogenesis.
• Accurate measurement of RAS-ERK pathway functional output is needed for clinical trial hypothesis testing.
• Current methods may not fully capture pathway activity or be suitable for routine clinical samples.

Purpose of the Study:

• To develop a clinically viable gene expression assay for RAS-ERK pathway output measurement in NSCLC.
• To optimize and validate NanoString-based assays for MEK and RAS gene signatures.
• To assess the utility of these signatures in identifying patient populations for targeted therapies.

Main Methods:

• Optimization of a published MEK functional activation signature for NSCLC.
• Development of NanoString assays for MEK and a 147-gene RAS signature.
• Validation in NSCLC cell lines and formalin-fixed paraffin-embedded tissue (FFPET) samples, assessing platform transfer, modulation, reproducibility, and association with KRAS mutation status.

Main Results:

• Strong cross-platform correlation and signature modulation observed in vitro.
• Consistent and robust signature scores in technical and biological replicates, showing conservation between primary and metastatic tumors.
• Statistically significant associations between high MEK and RAS signature scores and KRAS mutation status in 50 NSCLC samples.

Conclusions:

• A technically and biologically robust NanoString gene expression assay for MEK pathway output was developed, compatible with FFPET.
• The gene signatures identified distinct patient populations for MEK inhibitor treatment compared to KRAS mutation testing.
• Further clinical trial investigation of the MEK signature's predictive power is warranted.