Journal article
U. Pfohl, Jürgen Loskutov, S. Bashir, R. Kühn, Patrick Herter, M. Templin, S. Mamlouk, S. Belanov, M. Linnebacher, Florian Bürtin, Marcus Vetter, Christoph Reinhard, L. Wedeken, C. Regenbrecht
Cancers, 2022
Cancers, 2022
Semantic Scholar
DOI
PubMedCentral
PubMed
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Cite
APA
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Pfohl, U., Loskutov, J., Bashir, S., Kühn, R., Herter, P., Templin, M., … Regenbrecht, C. (2022). A RAS-Independent Biomarker Panel to Reliably Predict Response to MEK Inhibition in Colorectal Cancer. Cancers.
Chicago/Turabian
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Pfohl, U., Jürgen Loskutov, S. Bashir, R. Kühn, Patrick Herter, M. Templin, S. Mamlouk, et al. “A RAS-Independent Biomarker Panel to Reliably Predict Response to MEK Inhibition in Colorectal Cancer.” Cancers (2022).
MLA
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Pfohl, U., et al. “A RAS-Independent Biomarker Panel to Reliably Predict Response to MEK Inhibition in Colorectal Cancer.” Cancers, 2022.
BibTeX Click to copy
@article{u2022a,
title = {A RAS-Independent Biomarker Panel to Reliably Predict Response to MEK Inhibition in Colorectal Cancer},
year = {2022},
journal = {Cancers},
author = {Pfohl, U. and Loskutov, Jürgen and Bashir, S. and Kühn, R. and Herter, Patrick and Templin, M. and Mamlouk, S. and Belanov, S. and Linnebacher, M. and Bürtin, Florian and Vetter, Marcus and Reinhard, Christoph and Wedeken, L. and Regenbrecht, C.}
}
Abstract
Simple Summary Today, clinical management for the majority of cancer patients is still based on a “one-size-fits-all” approach. To improve the outcomes in the era of personalized medicine, it is essential to stratify patients based on established and novel biomarkers. In the present study, we investigated a SMAD4 loss-of-function mutation, which is associated with chemoresistance and decreased overall survival in colorectal cancer (CRC). To investigate the molecular mechanism behind the impact on drug response, we used CRISPR technology on patient-derived organoid models (PDOs) of CRC. We showed that PDOs with loss-of-function SMAD4 mutations are sensitive to MEK-inhibitors. Using a novel four-gene signature reliably predicts sensitivity towards MEK-inhibitors, regardless of the RAS and BRAF status. The present study is a significant step towards personalized cancer therapy by identifying a new biomarker. 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.
