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Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic ras is a dominant predictor for resistance

Ihle, NT and Lemos, R and Wipf, P and Yacoub, A and Mitchell, C and Siwak, D and Mills, GB and Dent, P and Kirkpatrick, DL and Powis, G (2009) Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic ras is a dominant predictor for resistance. Cancer Research, 69 (1). 143 - 150. ISSN 0008-5472

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Abstract

The novel phosphatidylinositol-3-kinase (PI3K) inhibitor PX-866 was tested against 13 experimental human tumor xenografts derived fromcell lines of various tissue origins. Mutant PI3K (PIK3CA) and loss of PTEN activity were sufficient, but not necessary, as predictors of sensitivity to the antitumor activity of the PI3K inhibitor PX-866 in the presence of wild-type Ras, whereas mutant oncogenic Ras was a dominant determinant of resistance, even in tumors with coexisting mutations in PIK3CA. The level of activation of PI3K signaling measured by tumor phosphorylated Ser473-Akt was insufficient to predict in vivo antitumor response to PX-866. Reverse-phase protein array revealed that the Ras-dependent downstream targets c-Myc and cyclin B were elevated in cell lines resistant to PX-866 in vivo. Studies using an H-Ras construct to constitutively and preferentially activate the three best-defined downstream targets of Ras, i.e., Raf, RalGDS, and PI3K, showed that mutant Ras mediates resistance through its ability to use multiple pathways for tumorigenesis. The identification of Ras and downstream signaling pathways driving resistance to PI3K inhibition might serve as an important guide for patient selection as inhibitors enter clinical trials and for the development of rational combinations with other molecularly targeted agents. ©2009 American Association for Cancer Research.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ihle, NT
Lemos, R
Wipf, Ppwipf@pitt.eduPWIPF
Yacoub, A
Mitchell, C
Siwak, D
Mills, GB
Dent, P
Kirkpatrick, DL
Powis, G
Date: 1 January 2009
Date Type: Publication
Journal or Publication Title: Cancer Research
Volume: 69
Number: 1
Page Range: 143 - 150
DOI or Unique Handle: 10.1158/0008-5472.can-07-6656
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0008-5472
MeSH Headings: Animals; Apoptosis--physiology; Cell Line, Transformed; Cell Line, Tumor; Drug Resistance, Neoplasm; Genes, ras; Gonanes--pharmacology; Humans; Mice; Mice, SCID; Mutation; Neoplasms--drug therapy; Neoplasms--enzymology; Neoplasms--genetics; Neoplasms--metabolism; PTEN Phosphohydrolase--metabolism; Phosphatidylinositol 3-Kinases--antagonists & inhibitors; Phosphatidylinositol 3-Kinases--genetics; Phosphatidylinositol 3-Kinases--metabolism; Protein Kinase Inhibitors--pharmacology; Signal Transduction; Xenograft Model Antitumor Assays; raf Kinases--metabolism; ral Guanine Nucleotide Exchange Factor--metabolism; ras Proteins--genetics; ras Proteins--metabolism
Other ID: NLM NIHMS79323, NLM PMC2613546
PubMed Central ID: PMC2613546
PubMed ID: 19117997
Date Deposited: 03 Jul 2013 14:29
Last Modified: 22 Jun 2021 12:55
URI: http://d-scholarship.pitt.edu/id/eprint/19217

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