Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors.
Everolimus is an orally administered mTOR inhibitor. The effect, and mechanism of action, of everolimus on lung cancers with an epidermal growth factor receptor (EGFR) mutation remain unclear. Four gefitinib-sensitive and -resistant cell lines were used in the present work. Growth inhibition was determined using the MTT assay. Transgenic mice carrying the EGFR L858R mutation were treated with everolimus (10 mg/kg/day), or vehicle alone, from 5 to 20 weeks of age, and were then sacrificed. To evaluate the efficacy of everolimus in prolonging survival, everolimus (10 mg/kg/day) or vehicle was administered from 5 weeks of age. The four cell lines were similarly sensitive to everolimus. Expression of phosphorylated (p) mTOR and pS6 were suppressed upon treatment with everolimus in vitro, whereas the pAKT level increased. The numbers of lung tumors with a long axis exceeding 1mm in the everolimus-treated and control groups were 1.9 ± 0.9 and 9.4 ± 3.2 (t-test, p<0.001), respectively. pS6 was suppressed during eve r olimus treatment. Although apoptosis and autophagy were not induced in everolimus-treated EGFR transgenic mice, angiogenesis was suppressed. The median survival time in the everolimus-treated group (58.0 weeks) was significantly longer than that in the control group (31.2 weeks) (logrank test, p<0.001). These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating EGFR gene mutation.
Department of Hematology, Oncology, and Respiratory Medicine, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Masayuki
M
Yasugi
Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan. Electronic address: ntakigaw@gmail.com.
Nagio
N
Takigawa
Department of Hematology, Oncology, and Respiratory Medicine, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan; Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan.
Nobuaki
N
Ochi
Department of Hematology, Oncology, and Respiratory Medicine, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Kadoaki
K
Ohashi
Department of Hematology, Oncology, and Respiratory Medicine, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Daijiro
D
Harada
Department of Hematology, Oncology, and Respiratory Medicine, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Takashi
T
Ninomiya
Department of Hematology, Oncology, and Respiratory Medicine, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Toshi
T
Murakami
Department of Hematology, Oncology, and Respiratory Medicine, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Yoshihiro
Y
Honda
Department of Hematology, Oncology, and Respiratory Medicine, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Eiki
E
Ichihara
Department of Hematology, Oncology, and Respiratory Medicine, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Mitsune
M
Tanimoto
Department of Hematology, Oncology, and Respiratory Medicine, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Katsuyuki
K
Kiura
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D000068338:Everolimus; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D038601:Ribosomal Protein S6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D050505:Mutant Proteins; D011799:Quinazolines; D038601:Ribosomal Protein S6; D000068338:Everolimus; C546843:mTOR protein, mouse; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D000077156:Gefitinib; D020123:Sirolimus
Adenocarcinoma; EGFR; Everolimus; Non-small cell lung cancer; mTOR