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Adv."],"published-print":{"date-parts":[[2026,9,4]]},"abstract":"<jats:p>\n                    Patients with neurofibromatosis type 1 develop Schwann cell tumors called neurofibromas that arise within peripheral nerves, driven by loss of neurofibromin and consequent increased RAS\/RAF\/MEK signaling. MEK inhibitors achieve partial responses for benign neurofibromas but are limited by toxicity and incomplete efficacy, necessitating alternative approaches. Using the\n                    <jats:italic toggle=\"yes\">Dhh-<\/jats:italic>\n                    Cre;\n                    <jats:italic toggle=\"yes\">Nf1<\/jats:italic>\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    neurofibroma mouse model, we found that genetic ablation of\n                    <jats:italic toggle=\"yes\">Kras<\/jats:italic>\n                    , but not\n                    <jats:italic toggle=\"yes\">Hras<\/jats:italic>\n                    , markedly reduced neurofibroma development, inhibited MAPK activation, and rescued disrupted Remak bundles that are a morphologic hallmark of neurofibromas. These findings reveal a RAS paralog\u2013specific requirement for KRAS in NF1-deficient neurofibroma initiation. Pharmacological KRAS inhibition with BI6674, an orally bioavailable KRAS\n                    <jats:sup>multi<\/jats:sup>\n                    inhibitor, reduced tumor volume and proliferation in established neurofibromas and remodeled the tumor immune microenvironment, decreasing macrophages and dendritic cells. Combining KRAS and MEK inhibition further enhanced tumor regression. These findings demonstrate that KRAS is essential for neurofibroma formation and represents a promising therapeutic target, supporting clinical evaluation of KRAS inhibition for neurofibromas in patients with neurofibromatosis type 1.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg3475","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:59:26Z","timestamp":1788371966000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["KRAS is required for plexiform neurofibroma formation and represents a targetable vulnerability in established tumors"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4402-1930","authenticated-orcid":true,"given":"Liang","family":"Hu","sequence":"first","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niousha","family":"Ahmari","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0445-3027","authenticated-orcid":true,"given":"Abby","family":"Schaeper","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2861-4736","authenticated-orcid":true,"given":"Jay","family":"Pundavela","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7712-3653","authenticated-orcid":true,"given":"Mi-Ok","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, UCSF, 1450 3rd Street, San Francisco, CA 94143, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5323-6995","authenticated-orcid":true,"given":"Eva","family":"Dombi","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4239-5659","authenticated-orcid":true,"given":"Jianqiang","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA."},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7702-3468","authenticated-orcid":true,"given":"Julia","family":"Brunmair","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim RCV GmbH &amp; 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