Regulating the response to targeted MEK inhibition in melanoma

Abstract

T he limitations of revolutionary new mutation-specific inhibitors of BRAFV600E include the universal recurrence seen in melanoma patients treated with this novel class of drugs. Recently, our lab showed that simultaneous activation of the Wnt/β-catenin signaling pathway and targeted inhibition of BRAF V600E by PLX4720 synergistically induces apoptosis across a spectrum of BRAF V600E melanoma cell lines. As a follow-up to that study, treatment of BRAF-mutant and NRAS-mutant melanoma lines with WNT3A and the MEK inhibitor AZD6244 also induces apoptosis. The susceptibility of BRAF-mutant lines and NRAS-mutant lines to apoptosis correlates with negative regulation of Wnt/β-catenin signaling by ERK/ MAPK signaling and dynamic decreases in abundance of the downstream scaffolding protein, AXIN1. Apoptosisresistant NRAS-mutant lines can sensitize to AZD6244 by pretreatment with AXIN1 siRNA, similar to what we previously reported in BRAF-mutant cell lines. Taken together, these findings indicate that NRAS-mutant melanoma share with BRAF-mutant melanoma the potential to regulate apoptosis upon MEK inhibition through WNT3A and dynamic regulation of cellular AXIN1. Understanding the cellular context that makes melanoma cells susceptible to this combination treatment will contribute to the study and development of novel therapeutic combinations that may lead to more durable responses.

Pathways and therapeutic targets in melanoma

“…Negative regulation of WNT/β-catenin signaling by MAPK pathway was confirmed in an additional study [141]. Treatment of BRAF-mutant and NRAS-mutant melanoma lines with WNT3A and the MEK inhibitor AZD6244 induces apoptosis.…”

“…Treatment of BRAF-mutant and NRAS-mutant melanoma lines with WNT3A and the MEK inhibitor AZD6244 induces apoptosis. The susceptibility of BRAF- and NRAS-mutant lines to apoptosis correlated with negative regulation of Wnt/β-catenin signaling by ERK/MAPK signaling and dynamic decreases in abundance of the downstream scaffolding protein, AXIN1 [141]. WNT inhibitors such as PRI-724 (inhibitor of interaction between β-catenin and CBP) and OMP-54F28 (a fusion protein antagonistic to Fzd8) are starting to enter clinical testing in tumors other than melanoma.…”

Molecular Pathways: Targeting NRAS in Melanoma and Acute Myelogenous Leukemia

“…Sorafenib and tivantinib, a MET tyrosine kinase receptor inhibitor, were used in 8 patients with NRAS -mutant melanoma, with 2 patients achieving a complete or partial response and 2 additional patients experiencing best responses of stable disease (61). Preclinical data also suggest that combining inhibitors of MEK and WNT signaling, as well as AKT/nuclear factor κB inhibition, may have value in NRAS -mutant melanoma (62, 63). Targeting the molecular chaperone heat shock protein 90 (HSP90) is one strategy that allows the simultaneous suppression of multiple downstream targets of RAS signaling.…”

Profile of selumetinib and its potential in the treatment of melanoma

“…Gopal et al have reported that the PI3K/AKT pathway plays a critical role in the antitumor efficacy of selumetinib in BRAF mutant melanoma, and inhibition of PI3K/AKT pathway results in synergistic antitumor activity with selumetinib 22. Because it has been reported that activation of Wnt/β-catenin signaling pathway inhibits tumor growth in mouse models of melanoma,23 the combinatorial effect of Wnt/β-catenin activation and selumetinib was examined 24. The combination of selumetinib and WNT3A, a ligand of Wnt/β-catenin pathway, induced apoptosis of melanoma cell lines harboring BRAF or NRAS mutations by degradation of AXIN1, a negative regulator of Wnt/β-catenin signaling 24.…”