{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:19:22Z","timestamp":1788963562925,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fujian Science and Technology Innovation Joint Fund Project","award":["2020Y9035"],"award-info":[{"award-number":["2020Y9035"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Resistance to BRAF inhibitors (BRAFi), alone or with MEK inhibitors (MEKi), limits durable responses in BRAF-mutant melanoma. To characterize resistance-associated cell-state evolution, we analyzed 674 melanoma cells from six mice bearing tumors from a single patient-derived BRAF V600E-mutant melanoma xenograft (PDX) lineage before treatment, during initial regression, at minimal residual disease, and at resistant regrowth. Unsupervised clustering based on a BRAF-centered network feature set comprising 2506 candidate genes identified six transcriptional states, which were characterized using transcriptomic analyses. Cluster 4 was detected exclusively at resistant regrowth, a phase marked by MAPK pathway reactivation, and exhibited enhanced JAK-STAT\/interferon signaling and increased STAT1, STAT2, IRF7, IRF9, and RELB regulon activities. Network inference predicted STAT1-BRAF and IRF7-MET regulatory links, suggesting candidate routes to MAPK reactivation through BRAF overexpression and MET-mediated bypass signaling. External analyses partially recapitulated the resistance-associated transcriptional program in independent melanoma cell-line datasets and yielded limited, inconclusive evidence for the predicted STAT1-BRAF association in public perturbation datasets. Cluster 2 represented a pre-existing proliferative state whose signature was associated with shorter progression-free survival in pretreatment clinical cohorts. Together, these findings distinguish a therapy-associated acquired-resistance state from a pre-existing proliferative resistance-associated state and nominate the predicted STAT1-BRAF and IRF7-MET links for functional validation.<\/jats:p>","DOI":"10.3390\/ijms27188031","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:02:48Z","timestamp":1788962568000},"page":"8031","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Predicted\u00a0STAT1-BRAF and IRF7-MET Regulatory Links Are Associated with MAPK Pathway Reactivation and Targeted Therapy Resistance in Melanoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2725-8319","authenticated-orcid":false,"given":"Hao","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, Institute of Precision Medicine, School of 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Precision Medicine, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China"},{"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1510-1093","authenticated-orcid":false,"given":"Jun","family":"He","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, Institute of Precision Medicine, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China"},{"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, 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