Targeting BRCAness in Gastric Cancer
Abstract
We performed the screen of gastric cancer cell lines for their sensitivity to small molecule inhibitors of PARP (rucaparib,talazoparib, olaparib, AZD2461) alone, or in combination with MEK inhibitors. We also generated a modified CRISPR system using dCas9-KRAB expressing variants of these cells, and validated them for CRISPRi screening. These reagents will next be used for a sensitization screen to PARPi, ATRi and MEKi treatment. In the drug response assays, cell lines differed dramatically in their sensitivity and resistance to these drugs. A subset of gastric cancer cells showed synergistic response to a combination of PARPi olaparib or talazoparib with MEK inhibitor GSK1120212(trametinib), while the other cells were resistant to one or to both PARPi and MEKi. The predictive mechanism of cellular response is currently under study. We compared DNA damage signaling in gastric cancer cell lines. Pretreatment of cells with MEKi abolished activation of ATM and BRCA1 induced by either PARPi or the DNA-damaging agent Etoposide. Synergistic cell lines displayed down regulation of DNA damage-induced phospho-H2Ax and phospho-ATM when pretreated with MEKi. This effect was pronounced higher when the cells were pretreated with a combination of PARPi and MEKi.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2017
- Accession Number
- AD1050852
Entities
People
- Alan Ashworth
- David Quigley
- Eric Collisson
- Evsevia Vakiani
- Janjigian Yelena
- Jefferson Woods
- Lawrence Fong
- Michael Korn
- Morgan E. Diolaiti
- Olga Mirzoeva
- Patrick O'leary
- Wei Wu
- Yaelle Tuvy
Organizations
- University of California, San Francisco