Preclinical evaluation and reverse phase protein Array-based profiling of PI3K and MEK inhibitors in endometrial carcinoma in vitro

Ozlem Aslan, Mattia Cremona, Clare Morgan, Lydia W. Cheung, Gordon B. Mills, Bryan T. Hennessy

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background: The phosphoinositide-3-kinase (PI3K) pathway is the most commonly activated pathway in cancers due to mutations at multiple nodes and loss of PTEN. Furthermore, in endometrial cancer (EC), PI3K and RAS/RAF/MEK/MAPK (RAS/MAPK herein) pathway mutations frequently co-exist. We examined the role of PI3K and RAS/MAPK pathway mutations in determining responsiveness to therapies targeted to these pathways in vitro in EC. Methods: 13 EC cell lines were profiled for their PI3K pathway and KRAS mutational and PTEN protein status and treated with one MEK- and two PI3K- targeted inhibitors alone and in combination. Expression and phosphorylation of 66 proteins were evaluated by Reverse-Phase-Protein-Array (RPPA) in 6 EC cell lines to identify signalling changes in these pathways in response to therapy. Results: PTEN protein loss and the absence of any tested pathway mutations are dominant negative predictors of sensitivity to MEK inhibition. KRAS-mutated cells were most sensitive to MEK inhibition, but significantly more resistant to PI3K inhibition than KRAS-wild-type cell lines. Combinations of PI3K and MEK inhibitors showed synergy or additivity in all but two cell lines tested. Treatment of KRAS-mutated cells with PI3K inhibitors and treatment of PTEN-low cells with a MEK inhibitor were most likely to induce activation of MEK/MAPK and AKT, respectively, likely indicative of feedback-loop regulation. Conclusions: MEK inhibition may be a promising treatment modality, not just for ECs with mutated KRAS, but also for those with retained PTEN. Up-regulation of MEK/MAPK signalling by PI3K inhibition, and up-regulation of AKT activation by MEK inhibition may serve as potential biomarkers of likely responsiveness to each inhibitor.

Original languageEnglish (US)
Article number168
JournalBMC cancer
Volume18
Issue number1
DOIs
StatePublished - Feb 9 2018
Externally publishedYes

Keywords

  • Biomarkers
  • Endometrial cancer
  • KRAS
  • MEK inhibitor
  • PI3K inhibitor
  • PIK3CA
  • PTEN loss
  • Protein signalling

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

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