Combined Inhibition of MEK and Plk1 Has Synergistic Antitumor Activity in NRAS Mutant Melanoma

Abstract

About one third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS driven malignancies barely impact overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Plk1 expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of MEK and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo and first mechanistic data, that a MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS driven melanoma. Since mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins.

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

“…Although BI6727 appeared promising as a monotherapy, in an effort to increase the efficacy of volasertib, it was also studied in combination with the MEK inhibitor Trematinib (JTP-74057) against cancer cells in vitro. The combination of drugs resulted in a dual G1 and G2-M arrest in an NRAS-mutant melanoma cell line (66). Additionally, cyclins D and E decreased whilst cyclin B and p21 increased and an overall reduction in melanoma growth was observed.…”

Targeting mutant NRAS signaling pathways in melanoma

“…In clinical trials, the PLK inhibitor volasertib was well tolerated but had poor tumor responses (Lin et al, 2014). While the clinical effects of monotherapy with PLK1 inhibitors has been disappointing, the addition of MEK inhibitors induced apoptosis in mutant NRAS melanoma both in vitro and in vivo (Posch et al, 2015). …”

Searching for the Chokehold of NRAS Mutant Melanoma

“…Current research suggests that the efficacy of this combination might be increased when tumor cells also have genetic aberrations increasing CDK4 activity such as loss of p16(INK4a) or amplifications of cyclin D1 (VanArsdale et al, 2015; Young et al, 2014). Another, yet experimental, combination blocking the MAPK and cell-cycle pathways targets MEK and the cell-cycle regulator Plk1, which effectively reduces growth of NRAS mutant melanoma xenografts independent of p16(INK4a) mutation status (Posch et al, 2015). …”