Authors: William H. Conrad, Reyna D. Swift, Travis L. Biechele, Rima M. Kulikauskas, Randall T. Moon and Andy J. Chien

William H. Conrad

The Howard Hughes Medical Institute; University of Washington; Seattle, WA USA; Department of Pharmacology; University of Washington; Seattle, WA USA

Reyna D. Swift

The Howard Hughes Medical Institute; University of Washington; Seattle, WA USA

Travis L. Biechele

Department of Medicine; Division of Dermatology; University of Washington; Seattle, WA USA; The Institute for Stem Cell and Regenerative Medicine; University of Washington; Seattle, WA USA

Rima M. Kulikauskas

Department of Medicine; Division of Dermatology; University of Washington; Seattle, WA USA; The Institute for Stem Cell and Regenerative Medicine; University of Washington; Seattle, WA USA

Randall T. Moon

The Howard Hughes Medical Institute; University of Washington; Seattle, WA USA; Department of Pharmacology; University of Washington; Seattle, WA USA; The Institute for Stem Cell and Regenerative Medicine; University of Washington; Seattle, WA USA

Andy J. Chien

Corresponding author: andchien@uw.edu
Department of Medicine; Division of Dermatology; University of Washington; Seattle, WA USA; The Institute for Stem Cell and Regenerative Medicine; University of Washington; Seattle, WA USA

Abstract:
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.

Received: July 10, 2012; Accepted: July 26, 2012; Published Online: August 16, 2012

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