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dc.contributor.authorRenshaw, J
dc.contributor.authorTaylor, KR
dc.contributor.authorBishop, R
dc.contributor.authorValenti, M
dc.contributor.authorDe Haven Brandon, A
dc.contributor.authorGowan, S
dc.contributor.authorEccles, SA
dc.contributor.authorRuddle, RR
dc.contributor.authorJohnson, LD
dc.contributor.authorRaynaud, FI
dc.contributor.authorSelfe, JL
dc.contributor.authorThway, K
dc.contributor.authorPietsch, T
dc.contributor.authorPearson, AD
dc.contributor.authorShipley, J
dc.date.accessioned2022-04-06T14:44:38Z
dc.date.available2022-04-06T14:44:38Z
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2013, 19 (21), pp. 5940 - 5951en
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5074
dc.identifier.eissn1557-3265en_US
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-13-0850en_US
dc.identifier.doi10.1158/1078-0432.ccr-13-0850
dc.description.abstract<h4>Purpose</h4>To provide rationale for using phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathway inhibitors to treat rhabdomyosarcomas, a major cause of pediatric and adolescent cancer deaths.<h4>Experimental design</h4>The prevalence of PI3K/MAPK pathway activation in rhabdomyosarcoma clinical samples was assessed using immunohistochemistry. Compensatory signaling and cross-talk between PI3K/MAPK pathways was determined in rhabdomyosarcoma cell lines following p110α short hairpin RNA-mediated depletion. Pharmacologic inhibition of reprogrammed signaling in stable p110α knockdown lines was used to determine the target-inhibition profile inducing maximal growth inhibition. The in vitro and in vivo efficacy of inhibitors of TORC1/2 (AZD8055), MEK (AZD6244), and P13K/mTOR (NVP-BEZ235) was evaluated alone and in pairwise combinations.<h4>Results</h4>PI3K pathway activation was seen in 82.5% rhabdomyosarcomas with coactivated MAPK in 36% and 46% of alveolar and embryonal subtypes, respectively. p110α knockdown in cell lines over the short and long term was associated with compensatory expression of other p110 isoforms, activation of the MAPK pathway, and cross-talk to reactivate the PI3K pathway. Combinations of PI3K pathway and MAP-ERK kinase (MEK) inhibitors synergistically inhibited cell growth in vitro. Treatment of RD cells with AZD8055 plus AZD6244 blocked reciprocal pathway activation, as evidenced by reduced AKT/ERK/S6 phosphorylation. In vivo, the synergistic effect on growth and changes in pharmacodynamic biomarkers was recapitulated using the AZD8055/AZD6244 combination but not NVP-BEZ235/AZD6244. Pharmacokinetic analysis provided evidence of drug-drug interaction with both combinations.<h4>Conclusions</h4>Dual PI3K/MAPK pathway activation and compensatory signaling in both rhabdomyosarcoma subtypes predict a lack of clinical efficacy for single agents targeting either pathway, supporting a therapeutic strategy combining a TORC1/2 with a MEK inhibitor.en_US
dc.formatPrint-Electronicen_US
dc.format.extent5940 - 5951en_US
dc.languageengen_US
dc.language.isoengen
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden
dc.subjectCell Line, Tumoren_US
dc.subjectAnimalsen_US
dc.subjectHumansen_US
dc.subjectRhabdomyosarcomaen_US
dc.subjectDisease Models, Animalen_US
dc.subjectMorpholinesen_US
dc.subjectBenzimidazolesen_US
dc.subjectMitogen-Activated Protein Kinasesen_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.subjectSignal Transductionen_US
dc.subjectEnzyme Activationen_US
dc.subjectDrug Synergismen_US
dc.subjectFemaleen_US
dc.subjectProto-Oncogene Proteins p21(ras)en_US
dc.subjectProto-Oncogene Proteins c-akten_US
dc.subjectGene Knockdown Techniquesen_US
dc.subjectPhosphatidylinositol 3-Kinasesen_US
dc.subjectClass I Phosphatidylinositol 3-Kinasesen_US
dc.subjectTOR Serine-Threonine Kinasesen_US
dc.titleDual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo.en
dc.typeJournal Article
dcterms.dateAccepted2013-07-30
rioxxterms.versionAMen
rioxxterms.versionofrecord10.1158/1078-0432.ccr-13-0850en
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Researchen_US
pubs.issue21en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Drug Development and Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Tumour Biology & Metastasis
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Drug Development and Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Paediatric Drug Development and Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublisheden_US
pubs.volume19en_US
pubs.embargo.termsNot knownen_US
icr.researchteamCancer Pharmacology & Stress Response (CPSR)
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
icr.researchteamTumour Biology & Metastasis
icr.researchteamPaediatric Drug Development and Clinical Trials
icr.researchteamGlioma Team
icr.researchteamSarcoma Molecular Pathology
dc.contributor.icrauthorShipley, Janeten_US
dc.contributor.icrauthorValenti, Melanieen_US
dc.contributor.icrauthorDe Haven Brandon, Alexisen_US
dc.contributor.icrauthorGowan, Sharonen_US
dc.contributor.icrauthorEccles, Suzanneen_US
dc.contributor.icrauthorRuddle, Ruthen_US
dc.contributor.icrauthorRaynaud, Florenceen_US
dc.contributor.icrauthorPearson, Andrewen_US
dc.contributor.icrauthorSelfe, Joannaen_US
dc.contributor.icrauthorTaylor, Kathrynen_US
dc.contributor.icrauthorThway, Khinen_US
dc.contributor.icrauthorJohnson, Sarahen_US


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