Lapatinib-induced NF-kappaB activation sensitizes triple-negative breast cancer cells to proteasome inhibitors.

Abstract

INTRODUCTION:

Triple-negative breast cancer (TNBC), a subtype of breast cancer with negative expressions of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is frequently diagnosed in younger women and has poor prognosis for disease-free and overall survival. Due to the lack of known oncogenic drivers for TNBC proliferation, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed.

METHODS:

Triple-negative breast cancer cell lines were treated with proteasome inhibitors in combination with lapatinib (a dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor). Their in vitro and in vivo viability was examined by MTT assay, clonogenic analysis, and orthotopic xenograft mice model. Luciferase reporter gene, immunoblot, and RT-qPCR, immunoprecipitation assays were used to investigate the molecular mechanisms of action.

RESULTS:

Our data showed that nuclear factor (NF)-κB activation was elicited by lapatinib, independent of EGFR/HER2 inhibition, in TNBCs. Lapatinib-induced constitutive activation of NF-κB involved Src family kinase (SFK)-dependent p65 and IκBα phosphorylations, and rendered these cells more vulnerable to NF-κB inhibition by p65 small hairpin RNA. Lapatinib but not other EGFR inhibitors synergized the anti-tumor activity of proteasome inhibitors both in vitro and in vivo. Our results suggest that treatment of TNBCs with lapatinib may enhance their oncogene addiction to NF-κB, and thus augment the anti-tumor activity of proteasome inhibitors.

CONCLUSIONS:

These findings suggest that combination therapy of a proteasome inhibitor with lapatinib may benefit TNBC patients.

• Authors: Yun-Ju Chen, Ming-Hsin Yeh, Meng-Chieh Yu, Ya-Ling Wei, Wen-Shu Chen, Jhen-Yu Chen, Chih-Yu Shih, Chih-Yen Tu, Chia-Hung Chen, Te-Chun Hsia, Pei-Hsuan Chien, Shu-Hui Liu, Yung-Luen Yu, Wei-Chien Huang
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 15 Issue 6 Pg. R108 (Nov 12 2013) ISSN: 1465-542X [Electronic] England
• PMID: 24216290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Boronic Acids
• NF-kappa B
• Proteasome Inhibitors
• Pyrazines
• Quinazolines
• Lapatinib
• Bortezomib
• Erlotinib Hydrochloride
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• I-kappa B Kinase
• Gefitinib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Boronic Acids (administration & dosage, pharmacology)
• Bortezomib
• ErbB Receptors (antagonists & inhibitors)
• Erlotinib Hydrochloride
• Female
• Gefitinib
• Humans
• I-kappa B Kinase (metabolism)
• Lapatinib
• Mice, SCID
• NF-kappa B (metabolism)
• Phosphorylation (drug effects)
• Proteasome Inhibitors (pharmacology)
• Pyrazines (administration & dosage, pharmacology)
• Quinazolines (administration & dosage, pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Triple Negative Breast Neoplasms (drug therapy, metabolism)
• Xenograft Model Antitumor Assays