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Background <p>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 <i>BRAF</i><sup><i>V600E</i></sup> 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.</p> Methods <p>Here, we established a living biobank of <i>BRAF</i><sup><i>V600E</i></sup> 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.</p> Results <p>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.</p> Conclusion <p>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.</p>

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BRAFV600E patient derived colon cancer organoids identify biomarkers of response to EGFR and BRAF inhibition and replicate clinical data

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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

摘要

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 BRAFV600E 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 BRAFV600E 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.