title: Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055).
abstract: The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy.
authors.affiliation: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: Sarah V
authors.initials: SV
authors.lastname: Holt
authors.forename: Armelle
authors.initials: A
authors.lastname: Logie
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.forename: Denis
authors.initials: D
authors.lastname: Alferez
authors.forename: Sarah
authors.initials: S
authors.lastname: Runswick
authors.forename: Sarah
authors.initials: S
authors.lastname: Fenton
authors.forename: Christine M
authors.initials: CM
authors.lastname: Chresta
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.forename: Jingchuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.forename: Sylvie M
authors.initials: SM
authors.lastname: Guichard
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009025:Morpholines / Q000008:administration & dosage*; D009154:Mutation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C117307:KRAS protein, human; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins