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| Item Type: | Article |
|---|---|
| Title: | A RAS-independent biomarker panel to reliably predict response to MEK inhibition in colorectal cancer |
| Creators Name: | Pfohl, U., Loskutov, J., Bashir, S., Kühn, R., Herter, P., Templin, M., Mamlouk, S., Belanov, S., Linnebacher, M., Bürtin, F., Vetter, M., Reinhard, C., Wedeken, L. and Regenbrecht, C.R.A. |
| 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 SMAD4(R361H) PDOs were subjected to drug screening, RNA-Sequencing, and multiplex protein profiling (DigiWest(R)). 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. |
| Keywords: | Organoids, Biomarker, Targeted Therapy, Colorectal Cancer, CRC, SMAD4, TGF-β/BMP-Pathway, Intra-Tumor Heterogeneity, MEK Inhibition |
| Source: | Cancers |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Volume: | 14 |
| Number: | 13 |
| Page Range: | 3252 |
| Date: | 1 July 2022 |
| Official Publication: | https://doi.org/10.3390/cancers14133252 |
| PubMed: | View item in PubMed |
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