A RAS-Independent Biomarker Panel to Reliably Predict Response to MEK Inhibition in Colorectal Cancer
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Updated: Sep 5, 2025
Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
Ulrike Pfohl1,2, Jürgen Loskutov1, Sanum Bashir3
1CELLphenomics GmbH, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
Abstract:
Background: In colorectal cancer (CRC), mutations of genes associated with the TGF-β/BMP signaling pathway, particularly affecting SMAD4, are known to correlate with decreased overall survival and it is assumed that this signaling axis plays a key role in chemoresistance. Methods: Using CRISPR technology on syngeneic patient-derived organoids (PDOs), we investigated the role of a loss-of-function of SMAD4 in sensitivity to MEK-inhibitors. CRISPR-engineered SMAD4R361H PDOs were subjected to drug screening, RNA-Sequencing, and multiplex protein profiling (DigiWest®). Initial observations were validated on an additional set of 62 PDOs with known mutational status. Results: We show that loss-of-function of SMAD4 renders PDOs sensitive to MEK-inhibitors. Multiomics analyses indicate that disruption of the BMP branch within the TGF-β/BMP pathway is the pivotal mechanism of increased drug sensitivity. Further investigation led to the identification of the SFAB-signature (SMAD4, FBXW7, ARID1A, or BMPR2), coherently predicting sensitivity towards MEK-inhibitors, independent of both RAS and BRAF status. Conclusion: We identified a novel mutational signature that reliably predicts sensitivity towards MEK-inhibitors, regardless of the RAS and BRAF status. This finding poses a significant step towards better-tailored cancer therapies guided by the use of molecular biomarkers.
Insights
Loss of SMAD4 function in colorectal cancer (CRC) makes tumors sensitive to MEK-inhibitors. A new SFAB-signature predicts this sensitivity, guiding targeted CRC therapies.
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.
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