biostudies-literatureUnknown29(2)Rebecca VWAlthough BRAF/MEK inhibitor (BRAFi/MEKi) therapy initially shows high efficacy in patients with <i>BRAF</i> ^{V600 E/K} cutaneous melanoma, resistance develops in over 75% of cases. We tested robustness of the umbrella trial strategy in this population by analyzing relationships between genomic status of a gene and associated downstream consequences at the protein level. The results revealed weak relationships among mutations, copy-number amplification, and protein expression and activation. An <i>in vivo</i> compound repurposing screen using 11 clinically relevant agents from an NCI-portfolio with pan-RTK, non-RTK, and/or PI3K-mTOR specificity identified dasatinib as most capable of restoring sensitivity to BRAFi/MEKi in patient-derived xenograft (PDX) models originating from tumors that had progressed on BRAFi ± MEKi. High baseline expression of BRAFi/MEKi resistance-associated proteins (e.g., AXL, YAP, HSP70, and phospho-AKT) was predictive of the response to BRAFi/MEKi + dasatinib combination therapy. These findings suggest that adding dasatinib may help overcome resistance and restore anti-tumor activity in patients with BRAFi/MEKi-refractory cutaneous melanoma.iScience114669https://www.ebi.ac.uk/biostudies/studies/S-EPMC12907876biostudies-literatureDasatinib resensitizes BRAF/MEK inhibitor efficacy in patient-derived xenografts from patients with progression on BRAF/MEK inhibitor treatment.PMC12907876Herlyn MRebecca VWLiu QWarrier GBrown GSGopal YNVDing JGoyal YToska EFane MEWei MGodok TKossenkov ACouts KLChen YAlicea GMFingerman DYin XJi HBravo JVillanueva JNathanson KXiao MArun KMDavies MAPortuallo MElad VfalseDasatinib resensitizes BRAF/MEK inhibitor efficacy in patient-derived xenografts from patients with progression on BRAF/MEK inhibitor treatment.Although BRAF/MEK inhibitor (BRAFi/MEKi) therapy initially shows high efficacy in patients with <i>BRAF</i> ^{V600 E/K} cutaneous melanoma, resistance develops in over 75% of cases. We tested robustness of the umbrella trial strategy in this population by analyzing relationships between genomic status of a gene and associated downstream consequences at the protein level. The results revealed weak relationships among mutations, copy-number amplification, and protein expression and activation. An <i>in vivo</i> compound repurposing screen using 11 clinically relevant agents from an NCI-portfolio with pan-RTK, non-RTK, and/or PI3K-mTOR specificity identified dasatinib as most capable of restoring sensitivity to BRAFi/MEKi in patient-derived xenograft (PDX) models originating from tumors that had progressed on BRAFi ± MEKi. High baseline expression of BRAFi/MEKi resistance-associated proteins (e.g., AXL, YAP, HSP70, and phospho-AKT) was predictive of the response to BRAFi/MEKi + dasatinib combination therapy. These findings suggest that adding dasatinib may help overcome resistance and restore anti-tumor activity in patients with BRAFi/MEKi-refractory cutaneous melanoma.2026-01-01T00:00:00Z2026 Feb2026-07-09T13:24:19.495Z2026-07-09T13:10:13.981ZS-EPMC129078764170476610.1016/j.isci.2026.114669