Phosphoproteomic analysis reveals PAK2 as a therapeutic target for lapatinib resistance in HER2-positive breast cancer cells

Yoojin Chang, Kyong Hwa Park, Ji Eun Lee, Ki Cheol Han

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The human epidermal growth factor receptor 2 (HER2)-positive breast cancer with overexpression of HER2 accounts for approximately 25% of breast cancers and is more aggressive than other types of breast cancer. Lapatinib has been widely used as a HER2-targeted therapy, however, a number of patients develop lapatinib resistance and still suffer from poor prognosis. Therefore, it is essential to identify novel therapeutic targets that could overcome lapatinib resistance. In this study, we carried out phosphoproteomic analysis of lapatinib sensitive and resistant cell lines (SKBR3 and SKBR3-LR) using stable isotope labeling with amino acids in cell culture (SILAC). We identified 3808 phosphopeptides from 1807 proteins and then analyzed signaling pathways, Gene Ontology, and protein-protein interaction networks. Finally, we identified PAK2 as a therapeutic target from the network analysis and validated that PAK2 knockdown and PAK inhibitor treatment resensitize the lapatinib resistant cells to lapatinib. This results suggest that PAK2 is a potent therapeutic target to overcome acquired lapatinib resistance in HER2-positive breast cancer cells.

Original languageEnglish
Pages (from-to)187-193
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume505
Issue number1
DOIs
Publication statusPublished - 2018 Oct 20

Fingerprint

Cells
Breast Neoplasms
Therapeutics
Isotope Labeling
Protein Interaction Maps
Phosphopeptides
Gene Ontology
Proteins
Electric network analysis
human ERBB2 protein
lapatinib
Cell culture
Isotopes
Labeling
Ontology
Cell Culture Techniques
Amino Acids
Cell Line

Keywords

  • HER2-Positive breast cancer
  • Lapatinib resistance
  • PAK2
  • Phosphoproteomics

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Phosphoproteomic analysis reveals PAK2 as a therapeutic target for lapatinib resistance in HER2-positive breast cancer cells. / Chang, Yoojin; Park, Kyong Hwa; Lee, Ji Eun; Han, Ki Cheol.

In: Biochemical and Biophysical Research Communications, Vol. 505, No. 1, 20.10.2018, p. 187-193.

Research output: Contribution to journalArticle

@article{3d4f53fc9c234d82af5f44f5aa96908a,
title = "Phosphoproteomic analysis reveals PAK2 as a therapeutic target for lapatinib resistance in HER2-positive breast cancer cells",
abstract = "The human epidermal growth factor receptor 2 (HER2)-positive breast cancer with overexpression of HER2 accounts for approximately 25{\%} of breast cancers and is more aggressive than other types of breast cancer. Lapatinib has been widely used as a HER2-targeted therapy, however, a number of patients develop lapatinib resistance and still suffer from poor prognosis. Therefore, it is essential to identify novel therapeutic targets that could overcome lapatinib resistance. In this study, we carried out phosphoproteomic analysis of lapatinib sensitive and resistant cell lines (SKBR3 and SKBR3-LR) using stable isotope labeling with amino acids in cell culture (SILAC). We identified 3808 phosphopeptides from 1807 proteins and then analyzed signaling pathways, Gene Ontology, and protein-protein interaction networks. Finally, we identified PAK2 as a therapeutic target from the network analysis and validated that PAK2 knockdown and PAK inhibitor treatment resensitize the lapatinib resistant cells to lapatinib. This results suggest that PAK2 is a potent therapeutic target to overcome acquired lapatinib resistance in HER2-positive breast cancer cells.",
keywords = "HER2-Positive breast cancer, Lapatinib resistance, PAK2, Phosphoproteomics",
author = "Yoojin Chang and Park, {Kyong Hwa} and Lee, {Ji Eun} and Han, {Ki Cheol}",
year = "2018",
month = "10",
day = "20",
doi = "10.1016/j.bbrc.2018.09.086",
language = "English",
volume = "505",
pages = "187--193",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Phosphoproteomic analysis reveals PAK2 as a therapeutic target for lapatinib resistance in HER2-positive breast cancer cells

AU - Chang, Yoojin

AU - Park, Kyong Hwa

AU - Lee, Ji Eun

AU - Han, Ki Cheol

PY - 2018/10/20

Y1 - 2018/10/20

N2 - The human epidermal growth factor receptor 2 (HER2)-positive breast cancer with overexpression of HER2 accounts for approximately 25% of breast cancers and is more aggressive than other types of breast cancer. Lapatinib has been widely used as a HER2-targeted therapy, however, a number of patients develop lapatinib resistance and still suffer from poor prognosis. Therefore, it is essential to identify novel therapeutic targets that could overcome lapatinib resistance. In this study, we carried out phosphoproteomic analysis of lapatinib sensitive and resistant cell lines (SKBR3 and SKBR3-LR) using stable isotope labeling with amino acids in cell culture (SILAC). We identified 3808 phosphopeptides from 1807 proteins and then analyzed signaling pathways, Gene Ontology, and protein-protein interaction networks. Finally, we identified PAK2 as a therapeutic target from the network analysis and validated that PAK2 knockdown and PAK inhibitor treatment resensitize the lapatinib resistant cells to lapatinib. This results suggest that PAK2 is a potent therapeutic target to overcome acquired lapatinib resistance in HER2-positive breast cancer cells.

AB - The human epidermal growth factor receptor 2 (HER2)-positive breast cancer with overexpression of HER2 accounts for approximately 25% of breast cancers and is more aggressive than other types of breast cancer. Lapatinib has been widely used as a HER2-targeted therapy, however, a number of patients develop lapatinib resistance and still suffer from poor prognosis. Therefore, it is essential to identify novel therapeutic targets that could overcome lapatinib resistance. In this study, we carried out phosphoproteomic analysis of lapatinib sensitive and resistant cell lines (SKBR3 and SKBR3-LR) using stable isotope labeling with amino acids in cell culture (SILAC). We identified 3808 phosphopeptides from 1807 proteins and then analyzed signaling pathways, Gene Ontology, and protein-protein interaction networks. Finally, we identified PAK2 as a therapeutic target from the network analysis and validated that PAK2 knockdown and PAK inhibitor treatment resensitize the lapatinib resistant cells to lapatinib. This results suggest that PAK2 is a potent therapeutic target to overcome acquired lapatinib resistance in HER2-positive breast cancer cells.

KW - HER2-Positive breast cancer

KW - Lapatinib resistance

KW - PAK2

KW - Phosphoproteomics

UR - http://www.scopus.com/inward/record.url?scp=85053666739&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053666739&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2018.09.086

DO - 10.1016/j.bbrc.2018.09.086

M3 - Article

VL - 505

SP - 187

EP - 193

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 1

ER -