The effect of dual inhibition of GSKβ and ATR on MDA-MB-231 cell viability

Candidate: Student Name
Supervisor: Dr. Sarah Sabatinos

ABSTRACT

Breast cancer is the most frequently diagnosed cancer among women, with a prevalence of 1 in 8 among Canadian women. Despite advancements in detection and treatment, breast cancer remains the leading cause of cancer-related mortality among women worldwide. Various therapeutic strategies target breast cancer, including interventions in DNA repair and metabolic pathways. In particular, the loss of Ataxia telangiectasia and Rad3-related kinase (ATR) impedes the cellular response to replication stress, while aberrant regulation of Glycogen Synthase Kinase 3β (GSK3β) has been implicated in breast cancer tumorigenesis. Although inhibition of either GSK3β or ATR individually may impact cancer cell viability, research examining the combined effects of dual GSK3β and ATR inhibition under replication stress on cell proliferation remains superficial. To address this gap, we investigated the impact of simultaneous inhibition on cell viability by comparing proportional cell death, cell cycle phase distribution, wound closure, and colony formation between wild-type and GSK3β knockout (KO) cells treated with ATR inhibitors under replication stress conditions. Our findings indicate that GSK3β loss combined with ATR inhibition did not significantly elevated DNA damage, yet when combined with replication stress, it led to heightened DNA damage, contributing to increased genomic instability.