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

被引:233
作者
Ihle, Nathan T. [1 ]
Lemos, Robert, Jr. [1 ]
Wipf, Peter [2 ]
Yacoub, Adly [3 ]
Mitchell, Clint [3 ]
Siwak, Doris [1 ]
Mills, Gordon B. [1 ]
Dent, Paul [3 ]
Kirkpatrick, D. Lynn [4 ]
Powis, Garth [1 ]
机构
[1] MD Anderson Canc Ctr, Houston, TX 77030 USA
[2] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA
[3] Virginia Commonwealth Univ, Sch Med, Richmond, VA USA
[4] Oncothyrcon Inc, Bellevue, WA USA
关键词
GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; PROTEIN-KINASE B; PHOSPHOINOSITIDE; 3-KINASE; TYROSINE KINASE; H-RAS; ACTIVATION; EXPRESSION; TRANSFORMATION; PROMOTES;
D O I
10.1158/0008-5472.CAN-07-6656
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The novel phosphatidylinositol-3-kinase (PI3K) inhibitor PX-866 was tested against 13 experimental human tumor xenografts derived from cell 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 Ser(473)-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 hest-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. [Cancer Res 2009;69(1):143-50]
引用
收藏
页码:143 / 150
页数:8
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