MEK and PI3K catalytic activity as predictor of the response to molecularly targeted agents in triple-negative breast cancer

• Published in: Biochemical and biophysical research communications 2017-08, Vol.489 (4), p.484-489
• Main Authors: Sato, Natsuki, Wakabayashi, Masayuki, Nakatsuji, Masatoshi, Kashiwagura, Haruka, Shimoji, Naohiro, Sakamoto, Shiho, Ishida, Atsuko, Lee, Jangsoon, Lim, Bora, Ueno, Naoto T., Ishihara, Hideki, Inui, Takashi
• Format: Article
• Language: English
• Subjects: Androstadienes - pharmacology; Animals; Antineoplastic Agents - pharmacology; Biocatalysis; Catalytic activity; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug sensitivity; Female; Humans; MEK; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; PI3K; Pyridones - pharmacology; Pyrimidinones - pharmacology; Structure-Activity Relationship; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Triple-negative breast cancer; Tumor Cells, Cultured; Wortmannin
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.05.177

Hyper-activation of the MAPK and PI3K-AKT pathways is linked to tumour progression in triple-negative breast cancer (TNBC). However, clinically effective predictive markers for drugs targeted against protein kinases involved in these pathways have not been identified. We investigated the ability of MEK and PI3K catalytic activity to predict sensitivity to trametinib and wortmannin in TNBC. MEK and PI3K activities correlated strongly with each other only in cell lines showing wortmannin-specific sensitivity, as shown by a linear regression curve (R = 0.951). Accordingly, we created a new parameter that distinguishes trametinib and wortmannin sensitivity in vitro and in vivo. Our findings suggest that the catalytic activities of MEK and PI3K might predict the response of TNBC to trametinib and wortmannin. •A new drug-sensitivity parameter based on kinase activities is proposed.•TNBC cells are classified into 4 groups based on MEK and PI3K inhibitor sensitivity.•Kinase assays for MEK and PI3K showed similar results in vitro and in vivo.