PI3K pathway dependencies in endometrioid endometrial cancer cell lines Journal Article

   


Authors: Weigelt, B.; Warne, P. H.; Lambros, M. B.; Reis-Filho, J. S.; Downward, J.
Article Title: PI3K pathway dependencies in endometrioid endometrial cancer cell lines
Abstract: 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 p110β 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, p110α, and p110β 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 p110β inhibitors GSK2636771 and AZD6482, and only in combination with the p110α selective inhibitor A66 was a decrease in cell viability observed. Conclusions: Targeted pan-PI3K andmTOR 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 p110β alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required. ©2013 AACR.
Journal Title: Clinical Cancer Research
Volume: 19
Issue: 13
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2013-07-01
Start Page: 3533
End Page: 3544
Language: English
DOI: 10.1158/1078-0432.ccr-12-3815
PROVIDER: scopus
PMCID: PMC3700760
PUBMED: 23674493
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84879848702&partnerID=40&md5=56401ac70ee0acd3501a70476f653cca
Notes: --- - "Export Date: 1 August 2013" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Britta Weigelt
    633 Weigelt
  2. Jorge Sergio Reis-Filho
    639 Reis-Filho
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