Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines.
The epidermal growth factor receptor (EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib resistance and able to maintain S6K phosphorylation after gefitinib treatment. Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity.
Department of Experimental Medicine, University of Parma, Via Volturno 39, 43100 Parma, Italy.
Silvia
S
La Monica
Maricla
M
Galetti
Roberta R
RR
Alfieri
Andrea
A
Cavazzoni
Andrea
A
Ardizzoni
Marcello
M
Tiseo
Marzia
M
Capelletti
Matteo
M
Goldoni
Sara
S
Tagliaferri
Antonio
A
Mutti
Claudia
C
Fumarola
Mara
M
Bonelli
Daniele
D
Generali
Pier Giorgio
PG
Petronini
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000068338:Everolimus; D000077156:Gefitinib; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D011799:Quinazolines; D000068338:Everolimus; D066246:ErbB Receptors; D019893:Ribosomal Protein S6 Kinases; D000077156:Gefitinib; D020123:Sirolimus