NDLI: The phosphoinositide-3-kinase inhibitor PX-866 overcomes resistance to the EGFR inhibitor gefitinib in A-549 human non small cell lung cancer xenografts.

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The phosphoinositide-3-kinase inhibitor PX-866 overcomes resistance to the EGFR inhibitor gefitinib in A-549 human non small cell lung cancer xenografts.

Inhibition of invasion, angiogenesis, tumor growth and metastasis by adenovirus-mediated transfer of antisense uPAR and MMP-9 in non-small cell lung cancer cells

Year: 2003, Volume: 2

The phosphoinositide-3-kinase inhibitor PX-866 overcomes resistance to the EGFR inhibitor gefitinib in A-549 human non small cell lung cancer xenografts.

Content Provider	PubMed Central
Author	Ihle, Nathan T. Gillian, Paine-murrieta Berggren, Margareta I. Baker, Amanda Tate, Wendy R. Wipf, Peter Abraham, Robert T. Kirkpatrick, D. Lynn Powis, Garth
Abstract	Epidermal growth factor receptor (EGFR) inhibitors such as gefitinib show antitumor activity in a subset of non small cell lung (nscl) cancer patients having mutated EGFR. Recent work shows that phosphatidylinositol-3-kinase (PtdIns-3-kinase) is coupled to the EGFR only in nscl cancer cell lines expressing ErbB-3 and that EGFR inhibitors do not inhibit PtdIns-3-kinase signaling in these cells. The central role PtdIns-3-kinase plays in cell survival suggests that a PtdIns-3-kinase inhibitor offers a strategy to increase the antitumor activity of EGFR inhibitors in resistant nscl tumors that do not express ErbB-3. We show that PX-866, a Ptdins-3-kinase inhibitor with selectivity for p110α, potentiates the antitumor activity of gefitinib against even large A-549 nscl xenografts giving complete tumor growth control in the early stages of treatment. A-549 xenograft phospho-Akt was inhibited by PX-866 but not by gefitinib. A major toxicity of PX-866 adminsitration was hyperglycemia with decreased glucose tolerance, which was reversed upon cessation of treatment. The decreased glucose tolerance caused by PX-866 was insensitive to the AMPK inhibitor metformin but reversed by insulin, and by the PPARγ activator pioglitazone. Prolonged PX-866 administration also caused increased neutrophil counts. Thus, PX-866, by inhibiting PtdIns-3-kinase signaling may have clinical utility in increasing the response to EGFR inhibitors such as gefitinib in patients with nscl cancer, and possibly in other cancers, who do not respond to EGFR inhibition.
Related Links	http://dx.doi.org/10.1158/1535-7163.mct-05-0149
Ending Page	1357
Page Count	9
Starting Page	1349
File Format	PDF
ISSN	15357163
e-ISSN	15388514
Journal	Molecular cancer therapeutics
Issue Number	9
Volume Number	4
Language	English
Publisher Date	2005-09-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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