{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:57:42Z","timestamp":1790625462965,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Cancer Biology","reference-count":84,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R00CA266920"],"award-info":[{"award-number":["R00CA266920"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Metastatic melanoma remains highly lethal despite advances in immunotherapy and MAPK-targeted therapy. The Rac1\n                  <jats:sup>P29S<\/jats:sup>\n                  mutation, present in 4-9% of cutaneous melanomas, confers intrinsic resistance to BRAF and MEK inhibitors. Like other small GTPases, Rac1 lacks suitable pockets for small molecule inhibitor binding, motivating indirect approaches to suppressing its activity. We have previously shown that wild-type Rac1 is sensitive to inhibition of\n                  <jats:italic>de novo<\/jats:italic>\n                  GTP biosynthesis in cancer cells, particularly suppression of the rate-limiting inosine monophosphate dehydrogenase (IMPDH) enzymes. Therefore, we asked whether IMPDH inhibition could suppress Rac1\n                  <jats:sup>P29S<\/jats:sup>\n                  and its associated phenotypes in melanoma. We found that IMPDH inhibition reduced Rac1 activity, impaired Rac1-dependent phenotypes, and induced S-phase arrest in Rac1\n                  <jats:sup>P29S<\/jats:sup>\n                  -harboring cells. Moreover, IMPDH inhibition synergized with the BRAF inhibitor vemurafenib and the MEK inhibitor trametinib in Rac1\n                  <jats:sup>P29S<\/jats:sup>\n                  melanoma cells. Dual BRAF and IMPDH inhibition also resulted in enhanced suppression of MEK and ERK phosphorylation in vitro. In syngeneic mouse models, the FDA-approved IMPDH inhibitor mycophenolate mofetil sensitized Rac1\n                  <jats:sup>P29S<\/jats:sup>\n                  -expressing melanoma tumors to trametinib, including tumors made refractory by prior trametinib exposure. We further identified a feed-forward circuit in which Rac1 sustains IMPDH2 expression levels through JNK and c-Jun\/AP1 signaling, potentially coupling the GTPase to its own nucleotide supply. These findings establish GTP biosynthesis as a targetable vulnerability in Rac1\n                  <jats:sup>P29S<\/jats:sup>\n                  melanoma and support IMPDH inhibition as a rational partner for MAPK-targeted therapy.\n                <\/jats:p>","DOI":"10.64898\/2026.09.23.753957","type":"posted-content","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:15:17Z","timestamp":1790270117000},"source":"Crossref","is-referenced-by-count":0,"title":["GTP biosynthesis is a therapeutic vulnerability in Rac1-mutant melanoma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0710-3857","authenticated-orcid":false,"given":"Samson","family":"Eugin Simon","sequence":"first","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiannan","family":"Wang","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arsha","family":"Sreekumar","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaria","family":"Yearby","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isha","family":"Patel","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varsha","family":"Tandra","sequence":"additional","affiliation":[{"name":"Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine C.","family":"Hedrick","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA"},{"name":"Immunology Center of Georgia, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4201-3857","authenticated-orcid":false,"given":"David W.","family":"Wolff","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA"},{"name":"Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092812151276000_2026.09.23.753957v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.017"},{"key":"2026092812151276000_2026.09.23.753957v1.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910836"},{"key":"2026092812151276000_2026.09.23.753957v1.3","doi-asserted-by":"crossref","first-page":"108200","DOI":"10.1016\/j.pharmthera.2022.108200","article-title":"The future of targeted kinase inhibitors in melanoma","volume":"239","year":"2022","journal-title":"Pharmacol Ther"},{"issue":"1-2","key":"2026092812151276000_2026.09.23.753957v1.4","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1053\/j.seminoncol.2023.03.003","article-title":"Improved outcomes in women with BRAF-mutant melanoma treated with BRAF\/MEK-targeted therapy across randomized clinical trials. 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