Dasatinib 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 BRAF 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 in vivo 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.