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ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma.
Hutchinson, Katherine E; Johnson, Douglas B; Johnson, Adam S; Sanchez, Violeta; Kuba, Maria; Lu, Pengcheng; Chen, Xi; Kelley, Mark C; Wang, Qingguo; Zhao, Zhongming; Kris, Mark; Berger, Michael F; Sosman, Jeffrey A; Pao, William.
Afiliación
  • Hutchinson KE; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Johnson DB; Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Johnson AS; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Sanchez V; Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Kuba M; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Lu P; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Chen X; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Kelley MC; Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Wang Q; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Zhao Z; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Kris M; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Berger MF; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
  • Sosman JA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
  • Pao W; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Oncotarget ; 6(26): 22348-60, 2015 Sep 08.
Article en En | MEDLINE | ID: mdl-26084293
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: MAP Quinasa Quinasa 1 / MAP Quinasa Quinasa 2 / Inhibidores de Proteínas Quinasas / Receptores ErbB / Melanoma Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Oncotarget Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: MAP Quinasa Quinasa 1 / MAP Quinasa Quinasa 2 / Inhibidores de Proteínas Quinasas / Receptores ErbB / Melanoma Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Oncotarget Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos