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This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Tumor samples (230) from a Norwegian national cohort undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations with clinical data were analyzed. mRNA sequencing was conducted on a subset of 30 samples to compare gene expression in tumors harboring <jats:italic>BRAF<\/jats:italic> or <jats:italic>KRAS<\/jats:italic> mutations and wild-type tumors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p><jats:italic>BRAF<\/jats:italic> mutations were detected in 27% of the patients, and the <jats:italic>BRAF<\/jats:italic>-mutated subgroup had inferior overall survival compared to wild-type cases (median 16 vs 36\u00a0months, respectively, p\u2009&lt;\u20090.001). <jats:italic>BRAF<\/jats:italic> mutations were associated with <jats:italic>RNF43<\/jats:italic>\/RSPO aberrations and low expression of negative Wnt regulators (ligand-dependent Wnt activation). Furthermore, <jats:italic>BRAF<\/jats:italic> mutations were associated with gene expression changes in transport solute carrier proteins (specifically <jats:italic>SLC7A6<\/jats:italic>) and drug metabolism enzymes (<jats:italic>CES1<\/jats:italic> and <jats:italic>CYP3A4<\/jats:italic>) that could influence the efficacy of MMC and irinotecan, respectively. <jats:italic>BRAF<\/jats:italic>-mutated tumors additionally exhibited increased expression of members of the novel butyrophilin subfamily of immune checkpoint molecules (<jats:italic>BTN1A1<\/jats:italic> and <jats:italic>BTNL9<\/jats:italic>).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p><jats:italic>BRAF<\/jats:italic> mutations were frequently detected and were associated with particularly poor survival in this cohort, possibly related to ligand-dependent Wnt activation and altered drug transport and metabolism that could confer resistance to MMC and irinotecan. Drugs that target ligand-dependent Wnt activation or the BTN immune checkpoints could represent two novel therapy approaches.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12967-024-05467-2","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T16:02:15Z","timestamp":1720540935000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Novel drug resistance mechanisms and drug targets in BRAF-mutated peritoneal metastasis from colorectal cancer"],"prefix":"10.1186","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7277-6612","authenticated-orcid":false,"given":"Christin","family":"Lund-Andersen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Torgunrud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chakravarthi","family":"Kanduri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vegar J.","family":"Dagenborg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida S.","family":"Fr\u00f8ysnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette M.","family":"Larsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Davidson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stein G.","family":"Larsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjersti","family":"Flatmark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,9]]},"reference":[{"issue":"6","key":"5467_CR1","first-page":"693","volume":"6","author":"H Guend","year":"2015","unstructured":"Guend H, Patel S, Nash GM. 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