Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer

BMC Cancer

Research Article

Lorenzo Memeo¹  Marc J. van de Vijver²  Hugo M. Horlings³  Mervi Jumppanen⁴  Yilun Chen⁵  Sofia K. Gruvberger-Saal⁶  Lao H. Saal⁷  Ying-Ka Ingar Lau⁸  Tao Su⁸  Matthew Maurer⁹  Hanina Hibshoosh^1,10  Meaghan Dendy^1,11  Ramon Parsons^1,12  Jorma Isola^1,13  Neal Rosen^1,14  Qing-Bai She^1,15 

[1] Department of Experimental Oncology, Mediterranean Institute of Oncology, Catania, Italy;Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands;Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands;Department of Pathology, Seinäjoki Central Hospital, Seinäjoki, Finland;Division of Oncology and Pathology, Clinical Sciences, Lund University, Lund, Sweden;Division of Oncology and Pathology, Clinical Sciences, Lund University, Lund, Sweden;Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA;Division of Oncology and Pathology, Clinical Sciences, Lund University, Lund, Sweden;Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA;Translational Oncogenomics Unit, Division of Oncology and Pathology, Lund University Cancer Center, Medicon Village 404-B2, SE-22381, Lund, Sweden;Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA;Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA;Department of Medicine, Columbia University, New York, NY, USA;Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA;Department of Pathology, Columbia University, New York, NY, USA;Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA;Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA;Department of Medicine, Columbia University, New York, NY, USA;Department of Pathology, Columbia University, New York, NY, USA;Department of Oncological Sciences and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Institute of Medical Technology, University of Tampere, Tampere, Finland;Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA;Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA;Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA;Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA;

关键词: Basal-like;    Breast cancer;    EGFR;    PTEN;    Combination therapy;   

DOI  :  10.1186/s12885-016-2609-2

 received in 2015-12-02, accepted in 2016-07-25,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated.MethodsOne hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively.ResultsSixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression.ConclusionsOur study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.

【 授权许可】

CC BY   
© The Author(s). 2016