61P - eIF4B as a novel target in EGFR expressing triple negative breast cancer

Date 08 May 2014
Event IMPAKT 2014
Session Welcome reception and Poster Walk
Topics Breast Cancer
Translational Research
Presenter Julie Madden
Citation Annals of Oncology (2014) 25 (suppl_1): i21-i22. 10.1093/annonc/mdu069
Authors J.M. Madden1, K. Mueller1, A. Bollig-Fischer2, P. Stemmer3, J. Boerner1
  • 1Oncology, Wayne State University, 48201 - Detroit/US
  • 2Bioinformatics, Wayne State University, 48201 - Detroit/US
  • 3Proteomics, Wayne State University, Detroit/US

Abstract

Triple negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive cancer that lacks an effective targeted therapeutic. Although many TNBCs, both in vitro and in vivo, have increased expression of epidermal growth factor receptor (EGFR), EGFR targeted inhibitors, such as gefitinib (Gef), have yet to demonstrate efficacy. Using mass spectrometry to identify pathways that remain activated in the presence of Gef, we found that components of the mTOR signaling pathway remain phosphorylated. While inhibiting mTOR with temsirolimus (Tem) decreased mTOR signaling, EGFR signaling pathways remained activated and the TNBC cell lines continued to proliferate. However, dual treatment with Tem and Gef synergistically decreased cell viability in TNBC cells. Interestingly, abrogation of both EGFR and mTOR signaling did not alter the phosphorylation of key growth signaling molecules including MAPK and AKT. Instead, our data have identified the translational control pathway, specifically, eIF4B as a potentially key regulatory point in EGFR and mTOR inhibitor synergy. Therefore, in this study we hypothesized that mTOR inhibition can sensitize TNBC cells to EGFR TKIs through the modulation of translational control. eIF4B enhances the helicase activity of eIF4A during translation initiation. As expected, knockdown of eIF4B expression decreased cell viability comparable to the decrease observed with the combination treatment. Importantly, we have identified p70S6K and p90RSK as kinases directly responsible for eIF4B phosphorylation, such that both molecules need to be inactivated in order for eIF4B phosphorylation to be abrogated. This inactivation correlated with a loss of cell growth and viability and a decrease in clonogenic cell survival, potentially through alterations in the cell cycle. Furthermore, cap-dependent translation was inhibited to a greater extent in the combination treatment than Gef or Tem alone. Taken together these data suggest that EGFR and mTOR inhibitor combination abrogates cell growth, viability, and survival via disruption of translational control mechanisms through eIF4B.

Disclosure:

All authors have declared no conflicts of interest.