Inhibition of the PI3K/AKT pathway potentiates cytotoxicity of EGFR kinase inhibitors in triple‐negative breast cancer cells

Journal of Cellular and Molecular Medicine

Yong Weon Yi³  Wooyoung Hong¹  Hyo Jin Kang³  Hee Jeong Kim³  Wenjing Zhao²  Antai Wang²  Yeon-Sun Seong¹ 

[1] Department of Nanobiomedical Science and WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea;Department of Biostatistics, Columbia University, New York, NY, USA;Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

关键词: triple‐negative breast cancers;    EGFR;    PI3K/AKT;    protein kinase inhibitors;    cytotoxicity;    synergism;   

DOI  :  10.1111/jcmm.12046

来源: Wiley

【 摘 要 】

Abstract

Triple-negative breast cancers (TNBCs) are known to be intrinsically resistant to inhibitors for epidermal growth factor receptor (EGFR). Until now, clinical trials for TNBCs using EGFR inhibitors (EGFRis) as single agents have yielded disappointing results. Here, we report that combinatorial treatment using EGFRis, such as gefitinib or erlotinib, with PI3K/AKT pathway inhibitors (PI3K/AKTis) demonstrated a synergistic, anti-proliferative effect in cell lines of the basal-like (BL) subtype, a subtype of TNBC. Western blot analysis revealed that the gefitinib/PI-103 combination significantly reduced the level of both phospho-AKT and phospho-ERK in two susceptible BL subtype cell lines, SUM149PT and MDA-MB-468, whereas it had little or no effect on the level of phospho-ERK in two non-susceptible cell lines (HS578T and MDA-MB-231) of mesenchymal stem-like (MSL) TNBC subtype. The gefitinib/PI-103 combination also significantly induced caspase-3/7-mediated PARP cleavage and reduced two anti-apoptotic proteins, XIAP and Bcl-2 in the susceptible cell lines. In addition, the level of myeloid cell leukemia 1 (Mcl-1) protein was markedly decreased by gefitinib/PI-103 combination in the BL TNBC cells, but showed no significant change by this combination in MSL subtype cells. These results suggest that pharmacological inhibition of EGFR used in combination of PI3K/AKTis is a potential therapeutic approach to treat a subtype of TNBCs.

【 授权许可】

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© 2013 The Authors Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd

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