PMID- 26084293 OWN - NLM STAT- MEDLINE DCOM- 20160927 LR - 20181202 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 6 IP - 26 DP - 2015 Sep 8 TI - ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma. PG - 22348-60 AB - 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. FAU - Hutchinson, Katherine E AU - Hutchinson KE AD - Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Johnson, Douglas B AU - Johnson DB AD - Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Johnson, Adam S AU - Johnson AS AD - Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Sanchez, Violeta AU - Sanchez V AD - Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Kuba, Maria AU - Kuba M AD - Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Lu, Pengcheng AU - Lu P AD - Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Chen, Xi AU - Chen X AD - Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Kelley, Mark C AU - Kelley MC AD - Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Wang, Qingguo AU - Wang Q AD - Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Zhao, Zhongming AU - Zhao Z AD - Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. AD - Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Kris, Mark AU - Kris M AD - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. FAU - Berger, Michael F AU - Berger MF AD - Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. AD - Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. FAU - Sosman, Jeffrey A AU - Sosman JA AD - Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Pao, William AU - Pao W AD - Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. AD - Currently an employee of Roche Pharma Research and Early Development, Basel, Switzerland. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - K12, CA-0906525/CA/NCI NIH HHS/United States GR - P30-CA008748/CA/NCI NIH HHS/United States GR - P01-CA129243/CA/NCI NIH HHS/United States GR - P01 CA129243/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.1.- (MAP2K2 protein, human) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) RN - EC 2.7.12.2 (MAP Kinase Kinase 2) RN - EC 2.7.12.2 (MAP2K1 protein, human) RN - EC 3.1.3.16 (Mitogen-Activated Protein Kinase Phosphatases) RN - EC 3.1.3.48 (DUSP4 protein, human) RN - EC 3.1.3.48 (Dual-Specificity Phosphatases) SB - IM MH - Cell Line, Tumor MH - Dual-Specificity Phosphatases/metabolism MH - ErbB Receptors/antagonists & inhibitors/*metabolism MH - Humans MH - MAP Kinase Kinase 1/*antagonists & inhibitors MH - MAP Kinase Kinase 2/*antagonists & inhibitors MH - Melanoma/*drug therapy/enzymology MH - Mitogen-Activated Protein Kinase Phosphatases/metabolism MH - Protein Kinase Inhibitors/*pharmacology MH - Proto-Oncogene Proteins c-akt/metabolism MH - Signal Transduction MH - Skin Neoplasms/enzymology PMC - PMC4673168 OTO - NOTNLM OT - DUSP4 OT - ERBB OT - afatinib OT - melanoma OT - trametinib COIS- CONFLICTS OF INTEREST J.A. Sosman has served on advisory boards for GlaxoSmithKline. M.C. Kelley has served on an advisory board for Amgen and receives research funding from GlaxoSmithKline via the National Comprehensive Cancer Network. EDAT- 2015/06/19 06:00 MHDA- 2016/09/28 06:00 PMCR- 2015/09/08 CRDT- 2015/06/19 06:00 PHST- 2015/04/09 00:00 [received] PHST- 2015/06/01 00:00 [accepted] PHST- 2015/06/19 06:00 [entrez] PHST- 2015/06/19 06:00 [pubmed] PHST- 2016/09/28 06:00 [medline] PHST- 2015/09/08 00:00 [pmc-release] AID - 4255 [pii] AID - 10.18632/oncotarget.4255 [doi] PST - ppublish SO - Oncotarget. 2015 Sep 8;6(26):22348-60. doi: 10.18632/oncotarget.4255.