Regulating the response to targeted MEK inhibition in melanoma: enhancing apoptosis in NRAS- and BRAF-mutant melanoma cells with Wnt/β-catenin activation.
The limitations of revolutionary new mutation-specific inhibitors of BRAF(V600E) 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. Apoptosis-resistant 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.
The Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
William H
WH
Conrad
Reyna D
RD
Swift
Travis L
TL
Biechele
Rima M
RM
Kulikauskas
Randall T
RT
Moon
Andy J
AJ
Chien
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D060466:Axin Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D060509:Wnt3A Protein / Q000494:pharmacology*; D051176:beta Catenin / Q000819:agonists / Q000235:genetics / Q000378:metabolism
C555451:AXIN1 protein, human; C517975:AZD 6244; D000970:Antineoplastic Agents; D060466:Axin Protein; D001562:Benzimidazoles; D007211:Indoles; C528407:PLX 4720; D034741:RNA, Small Interfering; D013449:Sulfonamides; D060509:Wnt3A Protein; D051176:beta Catenin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)