title: CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway.
abstract: The mammalian target of rapamycin (mTOR) is a potentially important therapeutic target in a broad range of cancer types. mTOR inhibitors such as rapamycin and its analogs (rapalogs) have been proven effective as anticancer agents in non-small cell lung cancer (NSCLC), whereas they strongly enhance phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and activation of Akt, which cause resistance to mTOR-targeted therapy after an initial response. Rapamycin induces eIF4E phosphorylation by activating MAPK-interacting kinases (Mnks), and therefore targeting Mnk/eIF4E pathway represents a potential therapeutic strategy for the treatment of NSCLC. Here, our results showed that over-expression of p-Mnk1 and p-eIF4E was significantly associated with poor overall survival of NSCLC patients and high expression of p-Mnk1 might act as an independent prognostic biomarker for these patients. Meanwhile, inhibiting Mnk1 expression by Mnk inhibitor (CGP57380) could abrogate rapalogs (RAD001)-induced eIF4E phosphorylation and Akt activation. Furthermore, combination of CGP57380 and RAD001 could induce NSCLC cells apoptosis via activating intrinsic mitochondrial pathway, and exert synergistic antitumor efficacy both in vitro and in vivo. In conclusion, combination of targeting both mTOR and Mnk/eIF4E signaling pathways to enhance effectiveness of mTOR-targeted cancer therapy might be significant innovation for the personalized treatment of NSCLC.
authors.affiliation: Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Qiuyuan
authors.initials: Q
authors.lastname: Wen
authors.affiliation: Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Weiyuan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Jiadi
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Shuzhou
authors.initials: S
authors.lastname: Chu
authors.affiliation: Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Hongjing
authors.initials: H
authors.lastname: Zang
authors.affiliation: Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Mohannad Ma
authors.initials: MM
authors.lastname: Alnemah
authors.affiliation: Cancer Research Institute of Central South University, Changsha, Hunan, 410078, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Songqing
authors.initials: S
authors.lastname: Fan
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D000068338:Everolimus / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D057285:Precision Medicine / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C466997:CGP 57380; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D011687:Purines; D000068338:Everolimus; C491395:MKNK1 protein, human; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Mnk1; apoptosis; eIF4E; mTOR; non-small cell lung cancer (NSCLC)