期刊
CLINICAL CANCER RESEARCH
卷 19, 期 13, 页码 3533-3544出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-12-3815
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资金
- Cancer Research UK
- Cancer Research UK [15680] Funding Source: researchfish
- Worldwide Cancer Research [13-0142] Funding Source: researchfish
Purpose: Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110 beta signaling for survival. Experimental Design: Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treated with pan-class I PI3K, p110 alpha, and p110 beta isoform-specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells. Results: EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110 beta inhibitors GSK2636771 and AZD6482, and only in combination with the p110 alpha selective inhibitor A66 was a decrease in cell viability observed. Conclusions: Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110 beta alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required. (C)2013 AACR.
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