BRAF(V600E) patient derived colon cancer organoids identify biomarkers of response to EGFR and BRAF inhibition and replicate clinical data

Kotarac, Anna; Osumi, Hiroki; Malt, Alexander; Alp, Keziban Merve; Jarosch, Armin; Werner, Johannes; Benary, Manuela; Neumann, Christopher C.M.; Yao, Ryoji; Mertins, Philipp; Eils, Roland; Beule, Dieter; Sers, Christine; Keilholz, Ulrich; Ishaque, Naveed; Stintzing, Sebastian; Vecchione, Loredana

BRAF(V600E) patient derived colon cancer organoids identify biomarkers of response to EGFR and BRAF inhibition and replicate clinical data

Tools

Preview	PDF (Accepted Manuscript) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader 3MB
	Other (Supplementary Information) 10MB

Item Type:	Article
Title:	BRAF(V600E) patient derived colon cancer organoids identify biomarkers of response to EGFR and BRAF inhibition and replicate clinical data
Creators Name:	Kotarac, Anna, Osumi, Hiroki, Malt, Alexander, Alp, Keziban Merve, Jarosch, Armin, Werner, Johannes, Benary, Manuela, Neumann, Christopher C.M., Yao, Ryoji, Mertins, Philipp, Eils, Roland, Beule, Dieter, Sers, Christine, Keilholz, Ulrich, Ishaque, Naveed, Stintzing, Sebastian and Vecchione, Loredana
Abstract:	BACKGROUND: Drug resistance and lack of predicting biomarkers are a major challenge for cancer therapy. The combination of a BRAF inhibitor (BRAFi) together with an anti-EGFR inhibitor (EGFRi) represents a standard of care approach in BRAF(V600E) metastatic colorectal cancer (mCRC) patients. However, predictive biomarkers of sensitivity, that could support patient selection for treatment with this combination, are currently missing. Therefore, our goal is to identify those biomarkers associated with response to the combination of BRAFi and EGFRi. METHODS: Here, we established a living biobank of BRAF(V600E) colorectal cancer patients derived organoids (PDOs) and categorized them as sensitive or resistant to the combination of BRAFi and EGFRi using short term proliferation assays. To elucidate biomarkers of response, drug testing was integrated with genomic, transcriptomic, proteomic and single-cell transcriptmic profiling of our PDOs. RESULTS: Here we revealed the PTEN/PIK3CA/p-AKT axis as mechanism of primary sensitivity while ROS pathway inhibition as driver for primary resistance. Finally, we newly discovered histology and cellular composition as biomarker of drug response. CONCLUSION: These data align with recently published clinical trial data, thus reinforcing the proof that PDOs can be used for biomarker identification. The use of histology and cellular compositions as biomarkers has to be further validated in clinical setting.
Keywords:	BRAF(V600E) Mutated Colorectal Cancer, Patient Derived Organoids, Drug Resistance, Encorafenib and Cetuximab, BRAF, PI3K, PTEN, AKT, ROS Pathway
Source:	Journal of Experimental & Clinical Cancer Research
ISSN:	1756-9966
Publisher:	BioMed Central / Association for the Promotion of International Tumor Studies
Date:	25 March 2026
Official Publication:	https://doi.org/10.1186/s13046-026-03699-2
PubMed:	View item in PubMed

Repository Staff Only: item control page

Download Statistics

Downloads

Downloads per month over past year