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

// Katherine E. Hutchinson 1 , Douglas B. Johnson 2 , Adam S. Johnson 3 , Violeta Sanchez 2 , Maria Kuba 3 , Pengcheng Lu 4 , Xi Chen 4 , Mark C. Kelley 5 , Qingguo Wang 6 , Zhongming Zhao 1, 6 , Mark Kris 7 , Michael F. Berger 8, 9 , Jeffrey A. Sosman 2 , William Pao 2, 10 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, USA 8 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA 9 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA 10 Currently 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.