Skip to main content

Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells.

Publication ,  Journal Article
Lidsky, M; Antoun, G; Speicher, P; Adams, B; Turley, R; Augustine, C; Tyler, D; Ali-Osman, F
Published in: J Biol Chem
October 3, 2014

Although targeting the V600E activating mutation in the BRAF gene, the most common genetic abnormality in melanoma, has shown clinical efficacy in melanoma patients, response is, invariably, short lived. To better understand mechanisms underlying this acquisition of resistance to BRAF-targeted therapy in previously responsive melanomas, we induced vemurafenib resistance in two V600E BRAF+ve melanoma cell lines, A375 and DM443, by serial in vitro vemurafenib exposure. The resulting approximately 10-fold more vemurafenib-resistant cell lines, A375rVem and D443rVem, had higher growth rates and showed differential collateral resistance to cisplatin, melphalan, and temozolomide. The acquisition of vemurafenib resistance was associated with significantly increased NRAS levels in A375rVem and D443rVem, increased activation of the prosurvival protein, AKT, and the MAPKs, ERK, JNK, and P38, which correlated with decreased levels of the MAPK inhibitor protein, GSTP1. Despite the increased NRAS, whole exome sequencing showed no NRAS gene mutations. Inhibition of all three MAPKs and siRNA-mediated NRAS suppression both reversed vemurafenib resistance significantly in A375rVem and DM443rVem. Together, the results indicate a mechanism of acquired vemurafenib resistance in V600E BRAF+ve melanoma cells that involves increased activation of all three human MAPKs and the PI3K pathway, as well as increased NRAS expression, which, contrary to previous reports, was not associated with mutations in the NRAS gene. The data highlight the complexity of the acquired vemurafenib resistance phenotype and the challenge of optimizing BRAF-targeted therapy in this disease. They also suggest that targeting the MAPKs and/or NRAS may provide a strategy to mitigate such resistance in V600E BRAF+ve melanoma.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

October 3, 2014

Volume

289

Issue

40

Start / End Page

27714 / 27726

Location

United States

Related Subject Headings

  • Vemurafenib
  • Up-Regulation
  • Tumor Cells, Cultured
  • Sulfonamides
  • Proto-Oncogene Proteins B-raf
  • Mutation, Missense
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Membrane Proteins
  • Melanoma
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lidsky, M., Antoun, G., Speicher, P., Adams, B., Turley, R., Augustine, C., … Ali-Osman, F. (2014). Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells. J Biol Chem, 289(40), 27714–27726. https://doi.org/10.1074/jbc.M113.532432
Lidsky, Michael, Gamil Antoun, Paul Speicher, Bartley Adams, Ryan Turley, Christi Augustine, Douglas Tyler, and Francis Ali-Osman. “Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells.J Biol Chem 289, no. 40 (October 3, 2014): 27714–26. https://doi.org/10.1074/jbc.M113.532432.
Lidsky M, Antoun G, Speicher P, Adams B, Turley R, Augustine C, et al. Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells. J Biol Chem. 2014 Oct 3;289(40):27714–26.
Lidsky, Michael, et al. “Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells.J Biol Chem, vol. 289, no. 40, Oct. 2014, pp. 27714–26. Pubmed, doi:10.1074/jbc.M113.532432.
Lidsky M, Antoun G, Speicher P, Adams B, Turley R, Augustine C, Tyler D, Ali-Osman F. Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells. J Biol Chem. 2014 Oct 3;289(40):27714–27726.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

October 3, 2014

Volume

289

Issue

40

Start / End Page

27714 / 27726

Location

United States

Related Subject Headings

  • Vemurafenib
  • Up-Regulation
  • Tumor Cells, Cultured
  • Sulfonamides
  • Proto-Oncogene Proteins B-raf
  • Mutation, Missense
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Membrane Proteins
  • Melanoma