Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling.

摘要: Melanoma is the most lethal form of skin cancer and successful treatment metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence resistance, whereas immunotherapy mainly effective in selected subsets patients. Thus, there need identify new targets improve melanoma. To this extent, we searched for markers that are elevated under regulation potentially druggable enzymes. Here, pro-proliferative transcription factor FOXM1 activated malignant activity correlated with expression enzyme Pin1, which found be indicative poor prognosis. In functional experiments, Pin1 proved main regulator through MEK-dependent physical during cell cycle. The Pin1-FOXM1 interaction was enhanced by BRAF(V600E), driver oncogene majority melanomas, extrapolation correlation data, interference with\ BRAF(V600E)-driven cells impaired both survival. Importantly, cell-permeable Pin1-FOXM1-blocking peptides repressed proliferation freshly isolated human ex vivo three-dimensional-cultured patient-derived melanoids. When combined BRAF(V600E)-inhibitor PLX4032 robust repression melanoid viability obtained, establishing preclinical value melanoids prognostic use drug sensitivity further underscoring beneficial effect inhibitory as anti-melanoma drugs. These proof-of-concept results provide starting point development therapeutic target