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, William Pao

Research output: Contribution to journalArticle

8 Scopus citations

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 pannegative 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.

Original languageEnglish (US)
Pages (from-to)22348-22360
Number of pages13
JournalOncotarget
Volume6
Issue number26
DOIs
StatePublished - 2015

Keywords

  • Afatinib
  • DUSP4
  • ERBB
  • Melanoma
  • Trametinib

ASJC Scopus subject areas

  • Oncology

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    Hutchinson, K. E., Johnson, D. B., Johnson, A. S., Sanchez, V., Kuba, M., Lu, P., Chen, X., Kelley, M. C., Wang, Q., Zhao, Z., Kris, M., Berger, M. F., Sosman, J. A., & Pao, W. (2015). ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma. Oncotarget, 6(26), 22348-22360. https://doi.org/10.18632/oncotarget.4255