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Tumor cells with KRAS or BRAF mutations or ERK5/MAPK7 amplification are not addicted to ERK5 activity for cell

Pamela A Lochhead1, Jonathan Clark2, Lan-Zhen Wang3

  • 1a Signalling Laboratory; The Babraham Institute ; Cambridge , UK.

Cell Cycle (Georgetown, Tex.)
|March 10, 2016
PubMed

Insights

Extracellular signal-regulated kinase 5 (ERK5) does not drive tumor cell proliferation downstream of RAS or BRAF mutations. Targeting ERK5 is unlikely to be an effective cancer therapy, even with MAPK7 amplification.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Extracellular signal-regulated kinase 5 (ERK5), encoded by MAPK7, is a potential cancer therapeutic target due to its proposed role in cell proliferation.
  • While oncogenic RAS/BRAF activate the MEK1/2-ERK1/2 pathway, ERK5 is activated by MEK5, with potential indirect activation by RAS/RAF proteins.
  • Understanding the interplay between RAS-RAF-MEK-ERK and ERK5 signaling is crucial for evaluating ERK5 as a cancer target.

Purpose of the Study:

  • To investigate the interplay between RAS-RAF-MEK-ERK and ERK5 signaling pathways.
  • To determine the role of ERK5 in tumor cell proliferation in relevant cancer models.
  • To assess the therapeutic potential of targeting ERK5 in cancers with RAS/BRAF mutations or MAPK7 amplification.

Main Methods:

  • Utilized an inducible form of CRAF (CRAF:ER*) in fibroblasts to study ERK5 activation.
  • Examined ERK5 activation in epithelial cells with oncogenic KRAS or BRAF mutations.
  • Assessed the effect of a selective MEK5 inhibitor (BIX02189) and ERK5 siRNA on colorectal cancer cell proliferation, alone and in combination with a MEK1/2 inhibitor (Selumetinib).
  • Investigated proliferation in cancer cells with MAPK7 amplification.

Main Results:

  • CRAF:ER* induced a delayed, feed-forward activation of ERK5 in fibroblasts, while oncogenic KRAS and BRAF did not directly activate ERK5 in epithelial cells.
  • Neither MEK5 inhibition (BIX02189) nor ERK5 knockdown (siRNA) inhibited proliferation of colorectal cancer cells harboring KRAS or BRAF mutations.
  • Combined MEK5 and MEK1/2 inhibition showed no additive or synergistic effects, indicating ERK5 is not required for proliferation or resistance to MEK1/2 inhibitors.
  • Cancer cells with MAPK7 amplification were resistant to BIX02189 and ERK5 siRNA, demonstrating no addiction to ERK5 for proliferation.

Conclusions:

  • ERK5 signaling is unlikely to play a significant role in tumor cell proliferation downstream of KRAS or BRAF mutations.
  • Targeting ERK5 is not a viable therapeutic strategy for colorectal cancers with KRAS/BRAF mutations or MAPK7 amplification.
  • These findings challenge the role of ERK5 as a direct anti-cancer drug target in these contexts.
Keywords:
BIX02189ERK5MEK5RAFRASselumetinibtumor cell proliferation

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