GTP biosynthesis is a therapeutic vulnerability in Rac1-mutant melanoma. (PubMed, bioRxiv) - Oct 2, 2026 - "Moreover, IMPDH inhibition synergized with the BRAF inhibitor vemurafenib and the MEK inhibitor trametinib in Rac1 P29S melanoma cells...In syngeneic mouse models, the FDA-approved IMPDH inhibitor mycophenolate mofetil sensitized Rac1 P29S -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 P29S melanoma and support IMPDH inhibition as a rational partner for MAPK-targeted therapy."
IO biomarker • Journal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • IMPDH2 • RAC1
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Arsha Sreekumar; Catherine C Hedrick; David W Wolff; Isha Patel; Jie Li; Samson Eugin Simon; Tiannan Wang; Varsha Tandra; Zaria Yearby
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