eLife, 2017-05, Vol.6
2017
Details
- Autor(en) / Beteiligte
- Titel
- Synergistic interactions with PI3K inhibition that induce apoptosis
- Ist Teil von
- eLife, 2017-05, Vol.6
- Ort / Verlag
- England: eLife Sciences Publications Ltd
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a mutant human breast cancer cell. We identified 5 genes ( ) whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2050-084XeISSN: 2050-084XDOI: 10.7554/eLife.24523Titel-ID: cdi_doaj_primary_oai_doaj_org_article_e53a69f812244f4b946e1569b458a6f8
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, Animals, Apoptosis, Breast cancer, Cancer Biology, Cell cycle, Cell death, Cell growth, Cell Line, Tumor, Cell Proliferation - drug effects, Cell survival, Cell Survival - drug effects, Disease Models, Animal, Drug Synergism, Enzyme Inhibitors - metabolism, Experiments, Flow cytometry, Genes, genome-scale shRNA screen, Genomes, Humans, Kinases, MAP Kinase Kinase Kinases, Mice, SCID, Mutation, Neoplasms, Experimental - therapy, Phosphoinositide-3 Kinase Inhibitors, PI3K inhibition, Protein Kinases - metabolism, Protein-Serine-Threonine Kinases - antagonists & inhibitors, Proto-Oncogene Proteins - antagonists & inhibitors, response modifying genes, siRNA, Standard deviation, Synergism, Transplantation, Heterologous, Treatment Outcome, Tumor cells, Tumors