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Loss of NF1 in MPNST leads to hyperactivation of RAS, however little is known about relevant downstream oncogenic signaling through RAF paralogs and effective targeted therapies in MPNST are still lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Conditional gene expression, CRISPR-CAS9, and shRNA-mediated knockdown were used to perform gain\/loss-of-function experiments to explore the effect of reconstituting the GTPase-activating protein-related domain of NF1 or knockdown of A\/B\/CRAF kinases on ERK signaling output and MPNST cell growth. Colony formation, cell proliferation and live cells imaging assays were performed to assess cell growth in response to genetic manipulations or drug treatments. Pathway enrichment analysis on RNA sequencing following drug perturbation, efficacy studies in cell-line-derived and patient-derived xenograft models, and immunoblotting\/immunohistochemistry were conducted to assess tumor growth and ERK pathway activity in cells or in pharmacodynamic analyses of tumor xenografts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NF1 loss activates RAS\/ERK signaling through B\/CRAF, and cell growth and ERK signaling of NF1-MPNST are dependent on B\/CRAF, but not ARAF. Genetic or pharmacological inhibition of B\/CRAF using a paralog-selective RAF inhibitor (RAFi) significantly potentiates MEK inhibitor (MEKi) treatment through more effective suppression of ERK signaling and proliferation. This is shown in multiple traditional and patient-derived cell line and xenograft models, including those with acquired resistance to MEKi.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings contribute preclinical evidence that the combination of paralog-selective B\/CRAFi and MEKi is effective in NF1-MPNST and can overcome resistance to single agent MEKi.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-025-01353-9","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T19:15:25Z","timestamp":1759173325000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Selective inhibition of BRAF and CRAF sensitizes NF1-deficient malignant peripheral nerve sheath tumors to MEK inhibitors"],"prefix":"10.1186","volume":"31","author":[{"given":"Jiawan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnab","family":"Sarkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindy","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Calizo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alla","family":"Lisok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Funan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishanth","family":"Punjaala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Marple","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Pollard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calixto-Hope G.","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesselina G.","family":"Cooke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Pratilas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelina V.","family":"Vaseva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"issue":"4","key":"1353_CR1","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1158\/1535-7163.MCT-07-0518","volume":"7","author":"G Ambrosini","year":"2008","unstructured":"Ambrosini G, Cheema HS, Seelman S, Teed A, Sambol EB, Singer S, et al. 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The approval of all experiments using patient-derived cell lines and xenografts was waived and such research use was covered in their respective original IRB protocols with written informed consent from participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics and consent to participate"}},{"value":"All authors reviewed the manuscript and consented to its publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Vesselina G. Cooke is an employee and stockholder of Novartis BioMedical Research (NBR). NBR provided LXH254\/ naporafenib and trametinib for testing in preclinical models under material transfer agreements to Johns Hopkins University (JHU) and UT Health San Antonio (UTHSCSA). JW and CAP have a pending patent (#US20240238284A1); CAP has an active patent (#US7812143B2), neither related to this study. AVV and VGC have a pending patent (#US20230321110A1), combination therapy of a RAF inhibitor and a MEK inhibitor for the treatment of sarcoma. The other authors have no additional conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"303"}}