Oncotarget

Research Papers:

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

Katherine E. Hutchinson _, Douglas B. Johnson, Adam S. Johnson, Violeta Sanchez, Maria Kuba, Pengcheng Lu, Xi Chen, Mark C. Kelley, Qingguo Wang, Zhongming Zhao, Mark Kris, Michael F. Berger, Jeffrey A. Sosman and William Pao

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Oncotarget. 2015; 6:22348-22360. https://doi.org/10.18632/oncotarget.4255

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Abstract

Katherine E. Hutchinson1, Douglas B. Johnson2, Adam S. Johnson3, Violeta Sanchez2, Maria Kuba3, Pengcheng Lu4, Xi Chen4, Mark C. Kelley5, Qingguo Wang6, Zhongming Zhao1,6, Mark Kris7, Michael F. Berger8,9, Jeffrey A. Sosman2, William Pao2,10

1Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

2Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

3Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

4Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA

5Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA

6Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA

7Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA

8Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA

9Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA

10Currently an employee of Roche Pharma Research and Early Development, Basel, Switzerland

Correspondence to:

Katherine E. Hutchinson, e-mail: katie.hutchinson@vanderbilt.edu

Keywords: melanoma, ERBB, DUSP4, trametinib, afatinib

Received: April 09, 2015     Accepted: June 01, 2015     Published: June 13, 2015

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.


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