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, NT and Paine-Murrieta, G and Berggren, MI and Baker, A and Tate, WR and Wipf, P and Abraham, RT and Kirkpatrick, DL and Powis, G (2005) 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. Molecular Cancer Therapeutics, 4 (9). 1349 - 1357. ISSN 1535-7163

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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. Copyright © 2005 American Association for Cancer Research.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Ihle, NT Paine-Murrieta, G Berggren, MI Baker, A Tate, WR Wipf, P pwipf@pitt.edu PWIPF Abraham, RT Kirkpatrick, DL Powis, G
Date:	1 September 2005
Date Type:	Publication
Journal or Publication Title:	Molecular Cancer Therapeutics
Volume:	4
Number:	9
Page Range:	1349 - 1357
DOI or Unique Handle:	10.1158/1535-7163.mct-05-0149
Schools and Programs:	Dietrich School of Arts and Sciences > Chemistry
Refereed:	Yes
ISSN:	1535-7163
MeSH Headings:	Animals; Antineoplastic Agents--pharmacology; Carcinoma, Non-Small-Cell Lung--drug therapy; Carcinoma, Non-Small-Cell Lung--metabolism; Carcinoma, Non-Small-Cell Lung--pathology; Drug Resistance, Neoplasm; Enzyme Inhibitors--pharmacology; Glucose Tolerance Test; Gonanes--pharmacology; Humans; Hyperglycemia--etiology; Hypoglycemic Agents--pharmacology; Lung Neoplasms--drug therapy; Lung Neoplasms--metabolism; Lung Neoplasms--pathology; Male; Metformin--pharmacology; Mice; Mice, SCID; Neutrophils--metabolism; Phosphatidylinositol 3-Kinases--antagonists & inhibitors; Phosphatidylinositol 3-Kinases--metabolism; Quinazolines--pharmacology; Receptor, Epidermal Growth Factor--antagonists & inhibitors; Thiazolidinediones--pharmacology; Transplantation, Heterologous; Tumor Cells, Cultured
Other ID:	NLM NIHMS9129, NLM PMC1432090
PubMed Central ID:	PMC1432090
PubMed ID:	16170026
Date Deposited:	17 Dec 2013 15:30
Last Modified:	02 Feb 2019 15:56
URI:	http://d-scholarship-dev.library.pitt.edu/id/eprint/19946

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