{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T02:20:44Z","timestamp":1791426044180,"version":"4.3.3"},"reference-count":43,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T00:00:00Z","timestamp":1728864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22K15555"],"award-info":[{"award-number":["JP22K15555"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:p>\n                    The Kirsten rat sarcoma (\n                    <jats:italic>KRAS<\/jats:italic>\n                    ) oncogene was considered \u201cundruggable\u201d until the development of sotorasib, a KRAS\n                    <jats:sup>G12C<\/jats:sup>\n                    selective inhibitor that shows favorable effects against lung cancers. MRTX1133, a novel KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    inhibitor, has shown promising results in basic research, although its effects against pancreatic cancer are limited when used alone. Therefore, there is an urgent need to identify effective drugs that can be used in combination with KRAS inhibitors. In this study, we found that administration of the KRAS inhibitors sotorasib or MRTX1133 upregulated STAT3 phosphorylation and reactivated ERK through a feedback reaction. The addition of the MEK inhibitor trametinib and the JAK2 inhibitor fedratinib successfully reversed this effect and resulted in significant growth inhibition\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Analyses of sotorasib\u2010 and MRTX1133\u2010resistant cells showed that trametinib plus fedratinib reversed the resistance to sotorasib or MRTX1133. These findings suggest that the JAK2\u2010mediated pathway and reactivation of the MAPK pathway may play key roles in resistance to KRAS inhibitors in pancreatic cancers. Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against\n                    <jats:italic>KRAS<\/jats:italic>\n                    \u2010mutant pancreatic cancer.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13751","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T04:28:36Z","timestamp":1728880116000},"page":"377-390","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Targeting\n                    <i>KRAS<\/i>\n                    \u2010mutant pancreatic cancer through simultaneous inhibition of\n                    <scp>KRAS<\/scp>\n                    ,\n                    <scp>MEK,<\/scp>\n                    and\n                    <scp>JAK2<\/scp>"],"prefix":"10.1002","volume":"19","author":[{"given":"Satoru","family":"Miyazaki","sequence":"first","affiliation":[{"name":"Division of Gastroenterological, Hepato\u2010Biliary\u2010Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7737-7592","authenticated-orcid":false,"given":"Masato","family":"Kitazawa","sequence":"additional","affiliation":[{"name":"Division of Gastroenterological, Hepato\u2010Biliary\u2010Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Division of Gastroenterological, Hepato\u2010Biliary\u2010Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine  Matsumoto 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