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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
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Phosphoproteomic analysis identifies activated MET-axis PI3K/AKT and MAPK/ERK in lapatinib-resistant cancer cell line

Yong Yook Lee1, Hwang-Phill Kim, Min Jueng Kang

  • 11] WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea [2] Wide River Institute of Immunology, Seoul National University, Seoul, Republic of Korea.

Experimental & Molecular Medicine
|November 23, 2013
PubMed

Insights

Lapatinib resistance in HER2-positive gastric cancer involves MET-dependent activation of PI3K/AKT and MAPK/ERK pathways. Restoring lapatinib sensitivity requires targeting these activated pathways alongside HER2 inhibition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Proteomics

Background:

  • Lapatinib, a dual inhibitor of EGFR and HER2, shows efficacy against HER2-positive cancers.
  • Acquired resistance to lapatinib is a significant clinical challenge in HER2-positive cancers.
  • Understanding resistance mechanisms is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying acquired lapatinib resistance in HER2-positive gastric cancer cells.
  • To compare the phosphoproteome of lapatinib-resistant (SNU216-LR) and parental (SNU216) gastric cancer cells.
  • To identify key signaling pathways involved in lapatinib resistance.

Main Methods:

  • Quantitative phosphoproteomics using TiO2 enrichment and Orbitrap mass spectrometry.
  • Biological network analysis of differentially expressed phosphoproteins.
  • Inhibition of identified signaling pathways (PI3K/AKT, MAPK/ERK) and assessment of lapatinib sensitivity.

Main Results:

  • Lapatinib-resistant cells exhibit constitutive activation of MET-axis PI3K/AKT and MAPK/ERK signaling pathways.
  • Inhibition of PI3K/AKT and MAPK/ERK pathways induces cell cycle arrest in resistant cells.
  • Combination therapy with lapatinib and other molecular agents restored sensitivity in resistant cells.

Conclusions:

  • MET-dependent activation of PI3K/AKT and MAPK/ERK pathways is a key mechanism of lapatinib resistance in gastric cancer.
  • Targeting these compensatory signaling pathways may overcome acquired resistance to lapatinib.
  • Phosphoproteomic analysis provides insights into intracellular signaling events driving drug resistance.

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