PLK1 and NOTCH Positively Correlate in Melanoma and Their Combined Inhibition Results in Synergistic Modulations of Key Melanoma Pathways

Abstract

Melanoma is one of the most serious forms of skin cancer, and its increasing incidence coupled with nonlasting therapeutic options for metastatic disease highlights the need for additional novel approaches for its management. In this study, we determined the potential interactions between polo-like kinase 1 (PLK1, a serine/threonine kinase involved in mitotic regulation) and NOTCH1 (a type I transmembrane protein deciding cell fate during development) in melanoma. Employing an in-house human melanoma tissue microarray (TMA) containing multiple cases of melanomas and benign nevi, coupled with high-throughput, multispectral quantitative fluorescence imaging analysis, we found a positive correlation between PLK1 and NOTCH1 in melanoma. Furthermore, The Cancer Genome Atlas database analysis of patients with melanoma showed an association of higher mRNA levels of PLK1 and NOTCH1 with poor overall, as well as disease-free, survival. Next, utilizing small-molecule inhibitors of PLK1 and NOTCH (BI 6727 and MK-0752, respectively), we found a synergistic antiproliferative response of combined treatment in multiple human melanoma cells. To determine the molecular targets of the overall and synergistic responses of combined PLK1 and NOTCH inhibition, we conducted RNA-sequencing analysis employing a unique regression model with interaction terms. We identified the modulations of several key genes relevant to melanoma progression/metastasis, including MAPK, PI3K, and RAS, as well as some new genes such as Apobec3G, BTK, and FCER1G, which have not been well studied in melanoma. In conclusion, our study demonstrated a synergistic antiproliferative response of concomitant targeting of PLK1 and NOTCH in melanoma, unraveling a potential novel therapeutic approach for detailed preclinical/clinical evaluation.

Necroptosis-associated classification combined with tumor microenvironment characteristic analysis of cutaneous melanoma

“…In addition, knockdown of PLK1 resulted in decreased clonal survival, cell cycle arrest, and apoptosis in melanoma cells. Su et al 42 reported that higher PLK1 levels were associated with worse OS and disease-free survival (DFS), which is consistent with our results. In addition, Deeraksa et al 45 demonstrated that PLK1 expression is elevated in androgen-insensitive prostate cancer (PCa) cells and silence of PLK1 promotes necroptosis-induced cell death in LNCaP-AI cells.…”

Present and Future Perspective on PLK1 Inhibition in Cancer Treatment

“…Again, the synergistic effect was due to cell cycle arrest and greater induction of apoptosis. Su et al found that the expression of PLK1 and NOTCH was associated with poor overall and disease-free survival in melanoma, and the combination of BI6727 with the NOTCH inhibitor MK0752 resulted in a synergistic antiproliferative response in BRAF mutated, BRAF and TP53 mutated, and NRAS mutated melanoma cells ( 170 ).…”

Piperine–Chlorogenic Acid Hybrid Inhibits the Proliferation of the SK-MEL-147 Melanoma Cells by Modulating Mitotic Kinases

“…Pathria et al [ 61 ] demonstrated that concomitant inhibition of AURKA/MEK might overcome resistance in NRAS -mutated melanomas, and Posch et al [ 62 ] reported that combination of MEK and PLK1 inhibitors suppresses proliferation of NRAS mutant melanoma cells in vitro and in vivo. In addition, it was revealed that PLK1 and NOTCH inhibitors had synergistic antiproliferative effect on multiple human melanoma cells [ 63 ].…”