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

Yong Weon Yi, Wooyoung Hong, Hyo Jin Kang, Hee Jeong Kim, Wenjing Zhao, Antai Wang, Yeon Sun Seong, Insoo Bae

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)648-656
Number of pages9
JournalJournal of Cellular and Molecular Medicine
Volume17
Issue number5
DOIs
StatePublished - May 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Cell Biology

Keywords

  • Cytotoxicity
  • EGFR
  • PI3K/AKT
  • Protein kinase inhibitors
  • Synergism
  • Triple-negative breast cancers

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