Abstract
Polo-like kinase 1 (PLK1), a critical cell cycle regulator, is associated with cancer progression and negatively correlates with patient survival in cutaneous melanoma based on clinical database analysis. In a melanoma mouse model induced by BRafCA mutation and Pten-deficiency, we observed that PLK1 overexpression mediated metabolic reprogramming to markedly accelerate tumor growth, promote metastasis, and shortened mice survival. Mechanistically, PLK1 stabilizes BTB domain and CNC homolog 1 (BACH1), which serves as a crucial transcription factor for genes involved in cancer metabolism and metastasis. Moreover, the PLK1/BACH1 axis confers resistance to Vemurafenib, a BRAFV600E inhibitor, in melanoma. In light of this finding, we attempted an innovative pharmacological combination targeting both BRAFV600E and PLK1, identifying a synergistic efficiency to this approach to suppress tumor growth. Overall, we have discovered a novel function of PLK1 that is independent of the cell cycle, which could pave new ways for melanoma therapies.