The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib

Highlights • AKT activation bypasses MEK inhibition in KRAS mutant NSCLC cells with intrinsic resistance to MEK inhibition. • AUY922 suppresses both PI3K-AKT-mTOR and RAF-MEK-ERK activation. • AUY922 sensitizes NSCLC cells with intrinsic resistance to MEK inhibitor trametinib.

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Bibliographische Detailangaben
Veröffentlicht in:	Cancer letters 2016-03, Vol.372 (1), p.75-81
Hauptverfasser:	Park, Kang-Seo, Oh, Bora, Lee, Mi-Hee, Nam, Ky-Youb, Jin, Hae Ran, Yang, Hannah, Choi, Junyoung, Kim, Sang-We, Lee, Dae Ho
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Apoptosis Cancer therapies Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - enzymology Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Cell Line, Tumor Cell Survival - drug effects Clinical trials Combination therapy Dose-Response Relationship, Drug Drug Resistance, Neoplasm Drug Synergism Female Hematology, Oncology and Palliative Medicine HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - metabolism HSP90 inhibitor Humans Immunoglobulins Isoxazoles - pharmacology Kinases KRAS mutation Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Lung Neoplasms - genetics Lung Neoplasms - pathology MEK inhibitor Melanoma Mice, Inbred BALB C Mice, Nude Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinase Kinases - metabolism Multiple myeloma Mutation NSCLC Protein Kinase Inhibitors - pharmacology Proteins Proto-Oncogene Proteins p21(ras) - genetics Pyridones - pharmacology Pyrimidinones - pharmacology Resorcinols - pharmacology Signal Transduction - drug effects Time Factors Tumor Burden - drug effects Tumors Xenograft Model Antitumor Assays
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Beschreibung
Zusammenfassung:	Highlights • AKT activation bypasses MEK inhibition in KRAS mutant NSCLC cells with intrinsic resistance to MEK inhibition. • AUY922 suppresses both PI3K-AKT-mTOR and RAF-MEK-ERK activation. • AUY922 sensitizes NSCLC cells with intrinsic resistance to MEK inhibitor trametinib.
ISSN:	0304-3835 1872-7980
DOI:	10.1016/j.canlet.2015.12.015