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Oncotarget. 2015 Sep 8;6(26):22348-60.

ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma.

Author information

1
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
2
Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
3
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
5
Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
6
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
7
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
8
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
9
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
10
Currently an employee of Roche Pharma Research and Early Development, Basel, Switzerland.

Abstract

Melanomas are characterized by activating "driver" mutations in BRAF, NRAS, KIT, GNAQ, and GNA11. Resultant mitogen-activated protein kinase (MAPK) pathway signaling makes some melanomas susceptible to BRAF (BRAF V600 mutations), MEK1/2 (BRAF V600, L597, fusions; NRAS mutations), or other kinase inhibitors (KIT), respectively. Among driver-negative ("pan-negative") patients, an unexplained heterogeneity of response to MEK1/2 inhibitors has been observed. Analysis of 16 pan-negative melanoma cell lines revealed that 8 (50%; termed Class I) are sensitive to the MEK1/2 inhibitor, trametinib, similar to BRAF V600E melanomas. A second set (termed Class II) display reduced trametinib sensitivity, paradoxical activation of MEK1/2 and basal activation of ERBBs 1, 2, and 3 (4 lines, 25%). In 3 of these lines, PI3K/AKT and MAPK pathway signaling is abrogated using the ERBB inhibitor, afatinib, and proliferation is even further reduced upon the addition of trametinib. A potential mechanism of ERBB activation in Class II melanomas is minimal expression of the ERK1/2 phosphatase, DUSP4, as ectopic restoration of DUSP4 attenuated ERBB signaling through potential modulation of the ERBB ligand, amphiregulin (AREG). Consistent with these data, immunohistochemical analysis of patient melanomas revealed a trend towards lower overall DUSP4 expression in pan-negative versus BRAF- and NRAS-mutant tumors. This study is the first to demonstrate that differential ERBB activity in pan-negative melanoma may modulate sensitivity to clinically-available MEK1/2 inhibitors and provides rationale for the use of ERBB inhibitors, potentially in combination with MEK1/2 inhibitors, in subsets of this disease.

KEYWORDS:

DUSP4; ERBB; afatinib; melanoma; trametinib

PMID:
26084293
PMCID:
PMC4673168
DOI:
10.18632/oncotarget.4255
[Indexed for MEDLINE]
Free PMC Article

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