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 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.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Hutchinson
authors.affiliation: Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Johnson
authors.affiliation: Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Violeta
authors.initials: V
authors.lastname: Sanchez
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kuba
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kelley
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kris
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.|Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Currently an employee of Roche Pharma Research and Early Development, Basel, Switzerland.
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D045744:Cell Line, Tumor; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology
chemical_list: D047428:Protein Kinase Inhibitors; C482128:MAP2K2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases
keywords: DUSP4; ERBB; afatinib; melanoma; trametinib