MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer

Persistent Link:
http://hdl.handle.net/10150/610342
Title:
MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer
Author:
Qi, Wenqing; Cooke, Larry; Stejskal, Amy; Riley, Christopher; Croce, Kimiko; Saldanha, Jose; Bearss, David; Mahadevan, Daruka
Affiliation:
Arizona Cancer Center, the University of Arizona, Tucson, AZ 85724, USA; National Institute for Medical Research, Mill Hill, London, UK; SuperGen, Inc, Dublin, CA 94568, USA
Issue Date:
2009
Publisher:
BioMed Central
Citation:
BMC Cancer 2009, 9:142 doi:10.1186/1471-2407-9-142
Journal:
BMC Cancer
Rights:
© 2009 Qi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
BACKGROUND:Prostate cancer is a common disease in men and at present there is no effective therapy available due to its recurrence despite androgen deprivation therapy. The epidermal growth factor receptor family (EGFR/HER1, HER2/neu and HER3)/PI3K/Akt signaling axis has been implicated in prostate cancer development and progression. However, Erlotinib, an EGFR tyrosine kinase inhibitor, has less effect on proliferation and apoptosis in prostate cancer cell lines. In this study, we evaluate whether MP470, a novel receptor tyrosine kinase inhibitor alone or in combination with Erlotinib has inhibitory effect on prostate cancer in vitro and in vivo.METHODS:The efficacy of MP470 or MP470 plus Erlotinib was evaluated in vitro using three prostate cancer cell lines by MTS and apoptosis assays. The molecular mechanism study was carried out by phosphorylation antibody array, immunoblotting and immunohistochemistry. A LNCaP mouse xenograft model was also used to determine the tumor growth inhibition by MP470, Erlotinib or the combination treatments.RESULTS:MP470 exhibits low muM IC50 in prostate cancer cell lines. Additive effects on both cytotoxicity and induction of apoptosis were observed when LNCaP were treated with MP470 in combination with Erlotinib. This combination treatment completely inhibited phosphorylation of the HER family members (HER1, 2, 3), binding of PI3K regulatory unit p85 to HER3 and downstream Akt activity even after androgen depletion. Furthermore, in a LNCaP mouse xenograft model, the MP470-Erlotinib combination produced 30-65% dose-dependent tumor growth inhibition (TGI).CONCLUSION:We propose that MP470-Erlotinib targets the HER family/PI3K/Akt pathway and may represent a novel therapeutic strategy for prostate cancer.
EISSN:
 1471-2407
DOI:
10.1186/1471-2407-9-142
Version:
Final published version
Additional Links:
http://www.biomedcentral.com/1471-2407/9/142

Full metadata record

DC FieldValue Language
dc.contributor.authorQi, Wenqingen
dc.contributor.authorCooke, Larryen
dc.contributor.authorStejskal, Amyen
dc.contributor.authorRiley, Christopheren
dc.contributor.authorCroce, Kimikoen
dc.contributor.authorSaldanha, Joseen
dc.contributor.authorBearss, Daviden
dc.contributor.authorMahadevan, Darukaen
dc.date.accessioned2016-05-20T09:04:41Z-
dc.date.available2016-05-20T09:04:41Z-
dc.date.issued2009en
dc.identifier.citationBMC Cancer 2009, 9:142 doi:10.1186/1471-2407-9-142en
dc.identifier.doi10.1186/1471-2407-9-142en
dc.identifier.urihttp://hdl.handle.net/10150/610342-
dc.description.abstractBACKGROUND:Prostate cancer is a common disease in men and at present there is no effective therapy available due to its recurrence despite androgen deprivation therapy. The epidermal growth factor receptor family (EGFR/HER1, HER2/neu and HER3)/PI3K/Akt signaling axis has been implicated in prostate cancer development and progression. However, Erlotinib, an EGFR tyrosine kinase inhibitor, has less effect on proliferation and apoptosis in prostate cancer cell lines. In this study, we evaluate whether MP470, a novel receptor tyrosine kinase inhibitor alone or in combination with Erlotinib has inhibitory effect on prostate cancer in vitro and in vivo.METHODS:The efficacy of MP470 or MP470 plus Erlotinib was evaluated in vitro using three prostate cancer cell lines by MTS and apoptosis assays. The molecular mechanism study was carried out by phosphorylation antibody array, immunoblotting and immunohistochemistry. A LNCaP mouse xenograft model was also used to determine the tumor growth inhibition by MP470, Erlotinib or the combination treatments.RESULTS:MP470 exhibits low muM IC50 in prostate cancer cell lines. Additive effects on both cytotoxicity and induction of apoptosis were observed when LNCaP were treated with MP470 in combination with Erlotinib. This combination treatment completely inhibited phosphorylation of the HER family members (HER1, 2, 3), binding of PI3K regulatory unit p85 to HER3 and downstream Akt activity even after androgen depletion. Furthermore, in a LNCaP mouse xenograft model, the MP470-Erlotinib combination produced 30-65% dose-dependent tumor growth inhibition (TGI).CONCLUSION:We propose that MP470-Erlotinib targets the HER family/PI3K/Akt pathway and may represent a novel therapeutic strategy for prostate cancer.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://www.biomedcentral.com/1471-2407/9/142en
dc.rights© 2009 Qi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)en
dc.titleMP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate canceren
dc.typeArticleen
dc.identifier.eissn 1471-2407en
dc.contributor.departmentArizona Cancer Center, the University of Arizona, Tucson, AZ 85724, USAen
dc.contributor.departmentNational Institute for Medical Research, Mill Hill, London, UKen
dc.contributor.departmentSuperGen, Inc, Dublin, CA 94568, USAen
dc.identifier.journalBMC Canceren
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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