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A RAS-independent biomarker panel to reliably predict response to MEK inhibition in colorectal cancer

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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. and Loskutov, J. and Bashir, S. and Kühn, R. and Herter, P. and Templin, M. and Mamlouk, S. and Belanov, S. and Linnebacher, M. and Bürtin, F. and Vetter, M. and Reinhard, C. and 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
Page Range:3252
Date:1 July 2022
Official Publication:https://doi.org/10.3390/cancers14133252
PubMed:View item in PubMed

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