The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts

Nathan T. Ihle, Gillian Paine-Murrieta, Margareta I. Berggren, Amanda F Baker, Wendy R. Tate, Peter Wipf, Robert T. Abraham, D. Lynn Kirkpatrick, Garth Powis

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

Epidermal growth factor receptor (EGFR) inhibitors such as gefitinib show antitumor activity in a subset of non - small cell lung cancer (NSCLC) patients having mutated EGFR. Recent work shows that phosphatidylinositol-3-kinase (PI3-K) is coupled to the EGFR only in NSCLC cell lines expressing ErbB-3 and that EGFR inhibitors do not inhibit PI3-K signaling in these cells.The central role PI3-K plays in cell survival suggests that a PI3-K 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 PI3-K inhibitor with selectivity for p1lα, 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 administration 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 AMP-activated protein kinase inhibitor metformin but reversed by insulin and by the peroxisome proliferator-activated receptor-γ activator pioglitazone. Prolonged PX-866 administration also caused increased neutrophil counts. Thus, PX-866, by inhibiting PI3-K signaling, may have clinical use in increasing the response to EGFR inhibitors such as gefitinib in patients with NSCLC and possibly in other cancers who do not respond to EGFR inhibition.

Original languageEnglish (US)
Pages (from-to)1349-1357
Number of pages9
JournalMolecular Cancer Therapeutics
Volume4
Issue number9
DOIs
StatePublished - Sep 2005

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Phosphatidylinositol 3-Kinase
Epidermal Growth Factor Receptor
Heterografts
Non-Small Cell Lung Carcinoma
pioglitazone
Glucose
Neoplasms
Peroxisome Proliferator-Activated Receptors
AMP-Activated Protein Kinases
Withholding Treatment
Metformin
Protein Kinase Inhibitors
gefitinib
PX-866
Hyperglycemia
Cell Survival
Neutrophils
Insulin
Cell Line
Growth

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. / Ihle, Nathan T.; Paine-Murrieta, Gillian; Berggren, Margareta I.; Baker, Amanda F; Tate, Wendy R.; Wipf, Peter; Abraham, Robert T.; Kirkpatrick, D. Lynn; Powis, Garth.

In: Molecular Cancer Therapeutics, Vol. 4, No. 9, 09.2005, p. 1349-1357.

Research output: Contribution to journalArticle

Ihle, Nathan T. ; Paine-Murrieta, Gillian ; Berggren, Margareta I. ; Baker, Amanda F ; Tate, Wendy R. ; Wipf, Peter ; Abraham, Robert T. ; Kirkpatrick, D. Lynn ; Powis, Garth. / The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. In: Molecular Cancer Therapeutics. 2005 ; Vol. 4, No. 9. pp. 1349-1357.
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