{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T12:33:10Z","timestamp":1786365190320,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,7]]},"group-title":"Cancer Biology","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Intramural Research Program of the National Institutes of Health","award":["ZIA BC 011732"],"award-info":[{"award-number":["ZIA BC 011732"]}]},{"name":"Intramural Research Program of the National Institutes of Health","award":["ZIA BC 011065"],"award-info":[{"award-number":["ZIA BC 011065"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Multiple myeloma (MM) is a plasma cell malignancy that frequently harbors activating mutations in\n                  <jats:italic>NRAS<\/jats:italic>\n                  and\n                  <jats:italic>KRAS<\/jats:italic>\n                  oncogenes. Previous clinical trials targeting the Ras\/MAPK oncogenic pathway with MEK inhibitors (MEKi) were met with limited efficacy, and newer generation of Ras inhibitors (RASi) have not been specifically evaluated in MM patients. To investigate the vulnerabilities of Ras-mutant MM to targeted therapies, we examined the sensitivity of a panel of human MM cell lines to the RASi RMC-6236 (daraxonrasib) and the MEKi trametinib. Although Ras-mutant MM cells are responsive to oncogenic Ras signaling and are sensitive to RAS inhibition, their sensitivity to MEK inhibition is heterogeneous. Mechanistic studies revealed that c-Myc protein is destabilized by MEK inhibition only in MEKi-sensitive MM cells but not in MEKi-resistant cells, and pharmacological and genetic stabilization of c-Myc is sufficient to confer MEKi resistance. In contrast, Ras inhibition reduced c-Myc protein across all MM cell lines tested, regardless of their dependency on the MAPK pathway, and c-Myc expression was insufficient to promote RASi resistance. Together, these findings demonstrate that c-Myc protein stability differentiates the response of Ras-mutant MM cells to Ras and MEK inhibition, and suggest that direct targeting of the Ras oncoprotein, rather than its downstream MAPK pathway, may present a more effective strategy.\n                <\/jats:p>","DOI":"10.64898\/2026.08.06.743109","type":"posted-content","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:35:14Z","timestamp":1786116914000},"source":"Crossref","is-referenced-by-count":0,"title":["Stability of c-Myc protein differentiates Ras oncogene addiction and MAPK pathway dependency in Ras-mutant multiple myeloma"],"prefix":"10.64898","author":[{"given":"Yeon-Hwa","family":"Lee","sequence":"first","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Cataisson","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Snehal","family":"Gaikwad","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy D.","family":"du Bois","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra M.","family":"Michalowski","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard H.","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Meyer","sequence":"additional","affiliation":[{"name":"Advanced Biomedical Computational Science, Frederick 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