Background The purpose of the study was to investigate a novel BRAF and CDK 4/6 inhibitor combination therapy in a murine model of BRAF-V600-mutant human melanoma monitored by .sup.18F-FDG-PET/CT and diffusion-weighted MRI (DW-MRI). Methods Human BRAF-V600-mutant melanoma (A375) xenograft-bearing balb/c nude mice (n = 21) were imaged by .sup.18F-FDG-PET/CT and DW-MRI before (day 0) and after (day 7) a 1-week BRAF and CDK 4/6 inhibitor combination therapy (n = 12; dabrafenib, 20 mg/kg/d; ribociclib, 100 mg/kg/d) or placebo (n = 9). Animals were scanned on a small animal PET after intravenous administration of 20 MBq .sup.18F-FDG. Tumor glucose uptake was calculated as the tumor-to-liver-ratio (TTL). Unenhanced CT data sets were subsequently acquired for anatomic coregistration. Tumor diffusivity was assessed by DW-MRI using the apparent diffusion coefficient (ADC). Anti-tumor therapy effects were assessed by ex vivo immunohistochemistry for validation purposes (microvascular density - CD31; tumor cell proliferation - Ki-67). Results Tumor glucose uptake was significantly suppressed under therapy (DELATTL.sub.Therapy - 1.00 + or - 0.53 vs. DELATTL.sub.Control 0.85 + or - 1.21; p 0.001). In addition, tumor diffusivity was significantly elevated following the BRAF and CDK 4/6 inhibitor combination therapy (DELAADC.sub.Therapy 0.12 + or - 0.14 x 10.sup.-3 mm.sup.2/s; DELAADC.sub.Control - 0.12 + or - 0.06 x 10.sup.-3 mm.sup.2/s; p 0.001). Immunohistochemistry revealed a significant suppression of microvascular density (CD31, 147 + or - 48 vs. 287 + or - 92; p = 0.001) and proliferation (Ki-67, 3718 + or - 998 vs. 5389 + or - 1332; p = 0.007) in the therapy compared to the control group. Conclusion A novel BRAF and CDK 4/6 inhibitor combination therapy exhibited significant anti-angiogenic and anti-proliferative effects in experimental human melanomas, monitored by .sup.18F-FDG-PET/CT and DW-MRI. Keywords: Melanoma, BRAF inhibitor, CDK inhibitor, .sup.18F-FDG-PET, Diffusion-weighted MRI, Therapy monitoring