Loss-of-function RNAi screens in breast cancer cells identify AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 as sensitizing targets of rapamycin activity

Oliver Ou, Konrad Huppi, Sirisha Chakka, Kristen Gehlhaus, Wendy Dubois, Jyoti Patel, Jinqiu Chen, Mark Mackiewicz, Tamara L. Jones, Jason J. Pitt, Scott E. Martin, Paul Goldsmith, John K. Simmons, Beverly A. Mock, Natasha J. Caplen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The use of molecularly targeted drugs as single agents has shown limited utility in many tumor types, largely due to the complex and redundant nature of oncogenic signaling networks. Targeting of the PI3K/AKT/mTOR pathway through inhibition of mTOR in combination with aromatase inhibitors has seen success in particular sub-types of breast cancer and there is a need to identify additional synergistic combinations to maximize the clinical potential of mTOR inhibitors. We have used loss-of-function RNAi screens of the mTOR inhibitor rapamycin to identify sensitizers of mTOR inhibition. RNAi screens conducted in combination with rapamycin in multiple breast cancer cell lines identified six genes, AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 that when silenced, each enhanced the sensitivity of multiple breast cancer lines to rapamycin. Using selective pharmacological agents we confirmed that inhibition of AURKB or PLK1 synergizes with rapamycin. Compound-associated gene expression data suggested histone deacetylation (HDAC) inhibition as a strategy for reducing the expression of several of the rapamycin-sensitizing genes, and we tested and validated this using the HDAC inhibitor entinostat in vitro and in vivo. Our findings indicate new approaches for enhancing the efficacy of rapamycin including the use of combining its application with HDAC inhibition.

Original languageEnglish (US)
Pages (from-to)336-347
Number of pages12
JournalCancer Letters
Volume354
Issue number2
DOIs
StatePublished - Nov 28 2014

Keywords

  • Breast cancer
  • HDAC inhibition
  • RNAi screen
  • Rapamycin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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