Abstract
The clinical success of EGFR inhibitors in patients with lung cancer is limited by the inevitable development of treatment resistance. Here, we show that inhibition of SREBP increase gefitinib sensitivity in vitro and in vivo. Interference of SREBP1 binding partner MARVELD1 potentiate the therapeutic effect of gefitinib as well. Mechanistically, SREBP inhibition decreases the cell membrane fluidity, results in a decreased tyrosine phosphorylation of EGFR. Therefore, targeting lipid metabolism combined with EGFR-TKIs is potentially a novel therapeutic strategies for cancer treatment.
Keywords:
SREBP; chemotherapy; gefitinib; lipid metabolism; lung cancer.
MeSH terms
-
Animals
-
Antineoplastic Agents / pharmacology*
-
Carcinoma, Non-Small-Cell Lung*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Drug Resistance, Neoplasm / drug effects*
-
Drug Synergism
-
Gefitinib
-
Humans
-
Hydroxycholesterols / pharmacology
-
Lung Neoplasms*
-
Membrane Proteins / metabolism
-
Mice
-
Mice, Nude
-
Microtubule-Associated Proteins / metabolism
-
Protein Kinase Inhibitors / pharmacology
-
Pyridines / pharmacology
-
Quinazolines / pharmacology
-
Signal Transduction / drug effects
-
Sterol Regulatory Element Binding Protein 1 / antagonists & inhibitors*
-
Thiazoles / pharmacology
-
Triterpenes / pharmacology
-
Xenograft Model Antitumor Assays
Substances
-
Antineoplastic Agents
-
Hydroxycholesterols
-
MARVELD1 protein, human
-
Membrane Proteins
-
Microtubule-Associated Proteins
-
Protein Kinase Inhibitors
-
Pyridines
-
Quinazolines
-
SREBF1 protein, human
-
Sterol Regulatory Element Binding Protein 1
-
Thiazoles
-
Triterpenes
-
fatostatin
-
betulin
-
25-hydroxycholesterol
-
Gefitinib