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

6 Citations (Scopus)

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 - Jan 1 2015
Externally publishedYes

Fingerprint

Melanoma
Mitogen-Activated Protein Kinases
Mutation
Proto-Oncogene Proteins B-raf
Phosphatidylinositol 3-Kinases
Phosphoric Monoester Hydrolases
Phosphotransferases
Ligands
Cell Line
trametinib
Neoplasms

Keywords

  • Afatinib
  • DUSP4
  • ERBB
  • Melanoma
  • Trametinib

ASJC Scopus subject areas

  • Oncology

Cite this

Hutchinson, K. E., Johnson, D. B., Johnson, A. S., Sanchez, V., Kuba, M., Lu, P., ... 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

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.

In: Oncotarget, Vol. 6, No. 26, 01.01.2015, p. 22348-22360.

Research output: Contribution to journalArticle

Hutchinson, KE, Johnson, DB, Johnson, AS, Sanchez, V, Kuba, M, Lu, P, Chen, X, Kelley, MC, Wang, Q, Zhao, Z, Kris, M, Berger, MF, Sosman, JA & Pao, W 2015, 'ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma', Oncotarget, vol. 6, no. 26, pp. 22348-22360. https://doi.org/10.18632/oncotarget.4255
Hutchinson KE, Johnson DB, Johnson AS, Sanchez V, Kuba M, Lu P et al. ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma. Oncotarget. 2015 Jan 1;6(26):22348-22360. https://doi.org/10.18632/oncotarget.4255
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. / ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma. In: Oncotarget. 2015 ; Vol. 6, No. 26. pp. 22348-22360.
@article{019b047bf4d14b6faaffd25fd49e0d50,
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 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.",
keywords = "Afatinib, DUSP4, ERBB, Melanoma, Trametinib",
author = "Hutchinson, {Katherine E.} and Johnson, {Douglas B.} and Johnson, {Adam S.} and Violeta Sanchez and Maria Kuba and Pengcheng Lu and Xi Chen and Kelley, {Mark C.} and Qingguo Wang and Zhongming Zhao and Mark Kris and Berger, {Michael F.} and Sosman, {Jeffrey A.} and William Pao",
year = "2015",
month = "1",
day = "1",
doi = "10.18632/oncotarget.4255",
language = "English (US)",
volume = "6",
pages = "22348--22360",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "26",

}

TY - JOUR

T1 - ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma

AU - Hutchinson, Katherine E.

AU - Johnson, Douglas B.

AU - Johnson, Adam S.

AU - Sanchez, Violeta

AU - Kuba, Maria

AU - Lu, Pengcheng

AU - Chen, Xi

AU - Kelley, Mark C.

AU - Wang, Qingguo

AU - Zhao, Zhongming

AU - Kris, Mark

AU - Berger, Michael F.

AU - Sosman, Jeffrey A.

AU - Pao, William

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

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 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.

KW - Afatinib

KW - DUSP4

KW - ERBB

KW - Melanoma

KW - Trametinib

UR - http://www.scopus.com/inward/record.url?scp=84941243540&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941243540&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.4255

DO - 10.18632/oncotarget.4255

M3 - Article

C2 - 26084293

AN - SCOPUS:84941243540

VL - 6

SP - 22348

EP - 22360

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 26

ER -