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P38 MAPK contributes to resistance and invasiveness of HER2- overexpressing breast cancer

S M Donnelly, E Paplomata, B M Peake

  • 1Department of Pharmacology, Emory University, Suite 5001, 1510 Clifton Rd., Atlanta, GA 30322. USA. RNAHTA@EMORY.EDU.

Current Medicinal Chemistry
|November 21, 2013
PubMed

Insights

p38 MAPK signaling drives resistance to trastuzumab therapy in HER2-overexpressing breast cancer. Inhibiting p38 MAPK can restore sensitivity and reduce invasiveness, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Intrinsic or acquired resistance to trastuzumab is a significant clinical challenge in HER2-overexpressing metastatic breast cancer.
  • Understanding the molecular mechanisms underlying this resistance is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To investigate the role of p38 MAPK signaling in trastuzumab resistance and invasiveness in HER2-overexpressing breast cancer.
  • To explore the relationship between Growth Differentiation Factor 15 (GDF15) and p38 MAPK activation in resistant cells.

Main Methods:

  • Utilized multiple models of intrinsic and acquired trastuzumab resistance.
  • Assessed the effect of p38 MAPK kinase inhibition and knockdown on trastuzumab sensitivity.
  • Investigated the impact of exogenous GDF15 and stable GDF15 overexpression on p38 phosphorylation and cell invasiveness.
  • Conducted immunohistochemical analysis on a breast tumor tissue array.

Main Results:

  • Increased phosphorylation of p38 MAPK was observed in models of both intrinsic and acquired trastuzumab resistance.
  • Inhibition or knockdown of p38 MAPK restored sensitivity to trastuzumab in resistant cell lines.
  • Exogenous or overexpressed GDF15 stimulated p38 phosphorylation and increased invasiveness in HER2-positive cells, an effect reversed by p38 inhibition.
  • A significant correlation was found between HER2, phosphorylated p38, and GDF15 positivity in breast tumor tissues.

Conclusions:

  • p38 MAPK signaling is a key driver of trastuzumab resistance and invasiveness in HER2-overexpressing breast cancer.
  • GDF15 may contribute to p38 activation in resistant cells, promoting a pro-invasive phenotype.
  • Targeting p38 MAPK represents a potential therapeutic strategy to overcome trastuzumab resistance.

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