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

Wenqing Qi, Larry S. Cooke, Amy Stejskal, Christopher Riley, Kimiko Della Croce, Jose W. Saldanha, David Bearss, Daruka Mahadevan

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 MP470or 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 μM 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.

Original languageEnglish (US)
Article number142
JournalBMC Cancer
Volume9
DOIs
StatePublished - May 11 2009
Externally publishedYes

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Receptor Protein-Tyrosine Kinases
Phosphatidylinositol 3-Kinases
Prostatic Neoplasms
Growth
Neoplasms
Apoptosis
Heterografts
Cell Line
Androgens
Phosphorylation
Therapeutics
Erlotinib Hydrochloride
MP470
Epidermal Growth Factor Receptor
Immunoblotting
Protein-Tyrosine Kinases
Inhibitory Concentration 50
Immunohistochemistry
Recurrence
Antibodies

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer. / Qi, Wenqing; Cooke, Larry S.; Stejskal, Amy; Riley, Christopher; Della Croce, Kimiko; Saldanha, Jose W.; Bearss, David; Mahadevan, Daruka.

In: BMC Cancer, Vol. 9, 142, 11.05.2009.

Research output: Contribution to journalArticle

Qi, Wenqing ; Cooke, Larry S. ; Stejskal, Amy ; Riley, Christopher ; Della Croce, Kimiko ; Saldanha, Jose W. ; Bearss, David ; Mahadevan, Daruka. / MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer. In: BMC Cancer. 2009 ; Vol. 9.
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AU - Qi, Wenqing

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AU - Stejskal, Amy

AU - Riley, Christopher

AU - Della Croce, Kimiko

AU - Saldanha, Jose W.

AU - Bearss, David

AU - Mahadevan, Daruka

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