A RAS-Independent Biomarker Panel to Reliably Predict Response to MEK Inhibition in Colorectal Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Mutations in the TGF-β/BMP signaling pathway, especially SMAD4, are linked to poor survival and chemoresistance in colorectal cancer (CRC).
• The TGF-β/BMP signaling axis is hypothesized to play a critical role in the development of chemoresistance in CRC.

Purpose of the Study:

• To investigate the impact of SMAD4 loss-of-function on MEK-inhibitor sensitivity in colorectal cancer.
• To identify molecular mechanisms and predictive biomarkers for MEK-inhibitor response in CRC.

Main Methods:

• Utilized CRISPR technology to engineer SMAD4 loss-of-function in patient-derived organoids (PDOs).
• Conducted drug screening, RNA-sequencing, and multiplex protein profiling (DigiWest®) on engineered PDOs.
• Validated findings on an independent cohort of 62 CRC PDOs with known mutational profiles.

Main Results:

• SMAD4 loss-of-function significantly increased sensitivity of CRC PDOs to MEK-inhibitors.
• Disruption of the BMP signaling pathway was identified as the key mechanism underlying enhanced drug sensitivity.
• Discovered the SFAB-signature (SMAD4, FBXW7, ARID1A, or BMPR2 mutations) as a predictor of MEK-inhibitor sensitivity, irrespective of RAS/BRAF status.

Conclusions:

• A novel SFAB-signature accurately predicts MEK-inhibitor sensitivity in colorectal cancer.
• This signature offers a biomarker-driven approach for personalized cancer therapy, independent of RAS/BRAF mutations.
• Findings advance the development of tailored CRC treatments utilizing molecular biomarkers.