Open AccessInhibition of the PI 3K/ AKT pathway potentiates cytotoxicity of EGFR kinase inhibitors in triple‐negative breast cancer cells
Author(s) -
Yi Yong Weon,
Hong Wooyoung,
Kang Hyo Jin,
Kim Hee Jeong,
Zhao Wenjing,
Wang Antai,
Seong YeonSun,
Bae Insoo
Publication year - 2013
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12046
Subject(s) - gefitinib , triple negative breast cancer , xiap , cancer research , protein kinase b , egfr inhibitors , erlotinib , epidermal growth factor receptor , mapk/erk pathway , cell growth , chemistry , biology , apoptosis , medicine , kinase , breast cancer , cancer , caspase , programmed cell death , biochemistry
Triple‐negative breast cancers ( TNBC s) are known to be intrinsically resistant to inhibitors for epidermal growth factor receptor ( EGFR ). Until now, clinical trials for TNBC s using EGFR inhibitors ( EGFR is) as single agents have yielded disappointing results. Here, we report that combinatorial treatment using EGFR is, such as gefitinib or erlotinib, with PI 3K/ AKT pathway inhibitors ( PI 3K/ AKT is) 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, SUM 149 PT and MDA ‐ MB ‐468, whereas it had little or no effect on the level of phospho‐ ERK in two non‐susceptible cell lines ( HS 578T 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 PI 3K/ AKT is is a potential therapeutic approach to treat a subtype of TNBC s.