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The combination of a BRAF inhibitor (BRAFi) together with an anti-EGFR inhibitor (EGFRi) represents a standard of care approach in\n                      <jats:italic>BRAF<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>V600E<\/jats:italic>\n                      <\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Here, we established a living biobank of\n                      <jats:italic>BRAF<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>V600E<\/jats:italic>\n                      <\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03699-2","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:34:09Z","timestamp":1774420449000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["BRAFV600E patient derived colon cancer organoids identify biomarkers of response to EGFR and BRAF inhibition and replicate clinical data"],"prefix":"10.1186","volume":"45","author":[{"given":"Anna","family":"Kotarac","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Osumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Malt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keziban Merve","family":"Alp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Jarosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Werner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Benary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C. 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Cell Syst. 2015;1(6):417\u201325. https:\/\/doi.org\/10.1016\/j.cels.2015.12.004.","journal-title":"Cell Syst"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-026-03699-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-026-03699-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-026-03699-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T20:49:01Z","timestamp":1781642941000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13046-026-03699-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3699"],"URL":"https:\/\/doi.org\/10.1186\/s13046-026-03699-2","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]},"assertion":[{"value":"2 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Human material for the establishement of model M2 was collected at Charite Universi\u00e4tsmedizin Berlin after patient consent within the \u201ccollection of tissue and blood samples for the tumor biobanking of the Charite Comprehensive Cancer Center, approved by the ethics committee of Charite Universi\u00e4tsmedizin Berlin-Campus Virchow Klinikum (EA1\/152\/10). Human material for the establishement of model ICP_CRC_01 was collected at Charite Universi\u00e4tsmedizin Berlin after patient consent within the \u201cInformativer Charite Patient\u201d (ICP) (Longitudinale Erhebung von Patienten-und Tumorcharakterstika bei Patienten mit gastrointestinalem Malignom mit einer Indikation zur Systemtherapie) trial, approved by the ethics committee of Charite Universi\u00e4tsmedizin Berlin (EA1\/161\/21).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"L.V. was supported by a grant from Pierre Fabre Pharma GmbH.. M.B. reports nonremunerated activities as a co-lead of the Virtual Molecular Tumor Board in the Variant Interpretation for Cancer Consortium (VICC) and as a co-organiser of the VICC\/ClinGen Somatic Case Studies in the ACMG. S.S. received honoraria for talks and advisory board commitments from AMGEN, AstraZeneca, Bayer, BMS, CV6, ESAI, Isofol, Janssen, Lilly, Merck KGaA Darmstadt, Germany, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, Takeda, and research grants from Merck KGaA, Darmstadt, Germany, Pierre-Fabre, Servier, Roche A.K., H.O., A.M., M.A., A.J., C.C.M.N., R.Y., P.M., R.E., D.B., C.S., U.K. and N.I. report none.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"92"}}