Targeting BRCAness in Gastric Cancer
Abstract
The goal of this project was to identify genes that drive resistance or sensitivity to PARP and/or ATR inhibition. Toward this end, we performed a pooled CRISPRi screen in the gastric cancer cell line AGS in the presence and absence of ATRi treatment. Our screen identified 57 potential genes whose knockdown induced ATRi resistance, including CDK2, which has an established role in ATRi resistance as well as multiple genes involved in RNA processing and stability. Top candidates were validated using an RNP mini-screen pipeline, and single cell clones of AGS cells lacking expression of candidate targets were generated for additional analysis including proteomic and transcriptomic studies. We used CRISPR-editing to knock out these genes in additional gastric cancer models to confirm if target loss is associated with ATRi sensitivity in different genetic contexts. To further evaluate these lead targets, we tested the sensitivity of these clones to a panel of approved oncology drugs. Additional experiments to uncover how RNA stability affects cellular response to ATRi are ongoing.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2018
- Accession Number
- AD1116869
Entities
People
- Alan Ashworth
- Patrick O'leary
Organizations
- University of California, San Francisco