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


Authors: Hutchinson, K. E.; Johnson, D. B.; Johnson, A. S.; Sánchez, V.; Kuba, M.; Lu, P.; Chen, X.; Kelley, M. C.; Wang, Q.; Zhao, Z.; Kris, M.; Berger, M. F.; Sosman, J. A.; Pao, W.
Article Title: ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma
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 pannegative 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: signal transduction; protein kinase b; controlled study; protein expression; protein phosphorylation; treatment response; unclassified drug; human cell; cell proliferation; cell viability; melanoma; mitogen activated protein kinase kinase 1; mitogen activated protein kinase kinase 2; epidermal growth factor receptor; epidermal growth factor receptor 2; bim protein; enzyme activation; enzyme activity; phosphatidylinositol 3 kinase; enzyme phosphorylation; mitogen activated protein kinase 1; mitogen activated protein kinase 3; upregulation; maximum plasma concentration; epidermal growth factor receptor 3; drug sensitivity; lapatinib; amphiregulin; rna sequence; dual specificity phosphatase; trametinib; afatinib; erbb; human; article; ic50; dusp4; dual specificity phosphatase 4
Journal Title: Oncotarget
Volume: 6
Issue: 26
ISSN: 1949-2553
Publisher: Impact Journals  
Date Published: 2015-09-08
Start Page: 22348
End Page: 22360
Language: English
PROVIDER: scopus
PUBMED: 26084293
DOI: 10.18632/oncotarget.4255
PMCID: PMC4673168
DOI/URL:
Notes: Export Date: 2 October 2015 -- Source: Scopus
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MSK Authors
  1. Michael Forman Berger
    409 Berger
  2. Mark Kris
    629 Kris