Detection of COPB2 as a KRAS synthetic lethal partner through integration of functional genomics screens

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

Abstract

Mutated KRAS plays an important role in many cancers. Although targeting KRAS directly is difficult, indirect inactivation via synthetic lethal partners (SLPs) is promising. Yet to date, there are no SLPs from high-throughput RNAi screening, which are supported by multiple screens. Here, we address this problem by aggregating and ranking data over three independent high-throughput screens. We integrate rankings by minimizing the displacement and by considering established methods such as RIGER and RSA.Our meta analysis reveals COPB2 as a potential SLP of KRAS with good support from all three screens. COPB2 is a coatomer subunit and its knock down has already been linked to disabled autophagy and reduced tumor growth. We confirm COPB2 as SLP in knock down experiments on pancreas and colorectal cancer cell lines.Overall, consistent integration of high throughput data can generate candidate synthetic lethal partners, which individual screens do not uncover. Concretely, we reveal and confirm that COPB2 is a synthetic lethal partner of KRAS and hence a promising cancer target. Ligands inhibiting COPB2 may, therefore, be promising new cancer drugs.

Details

OriginalspracheEnglisch
Seiten (von - bis)34283-34297
Seitenumfang15
FachzeitschriftOncotarget
Jahrgang8
Ausgabenummer21
PublikationsstatusVeröffentlicht - 23 Mai 2017
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC5470967
Scopus 85019952357
ORCID /0000-0003-2848-6949/work/141543370

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Cell Line, Tumor, Coatomer Protein/genetics, Colorectal Neoplasms/genetics, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Genomics/methods, High-Throughput Screening Assays, Humans, Neoplasms/genetics, Pancreatic Neoplasms/genetics, Proto-Oncogene Proteins p21(ras)/genetics, RNA Interference

Bibliotheksschlagworte