Chemo-phosphoproteomic profiling with ATR inhibitors berzosertib and gartisertib uncovers new biomarkers and DNA damage response regulators

Abstract

The ATR kinase protects cells against DNA damage and replication stress and represents a promising anti-cancer drug target. The ATR inhibitors (ATRi) berzosertib and gartisertib are in clinical trials for treatment of advanced solid tumours as monotherapy or in combination with genotoxic agents. However, the pharmacodynamic ATR biomarker phospho-CHK1 has shown limited sensitivity in for quantitative assessment of ATR activity in clinical trials. Therefore, better biomarkers are needed, and with this in mind we carried out quantitative phospho-proteomic screening for ATR biomarkers that are highly sensitive to berzosertib and gartisertib. Screening identified novel ATR-dependent targets in three broad classes: i) targets whose phosphorylation is highly sensitive to ATRi; ii) novel targets with known genome maintenance roles; iii) novel targets whose cellular roles are unclear, including SCAF1. We show that SCAF1 interacts with RNAPII in a phospho-dependent manner and suppresses homologous recombination in cells lacking the BRCA1 tumour suppressor. Taken together these data reveal potential new ATR biomarkers and new genome maintenance factors.

Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response

“…In a recent pre-print, Jadav et al investigated the MoA of Berzosertib and Gartisertib in US-O2 osteosarcoma cells treated with hydroxyurea 65 . Despite many differences in, for instance, the drug used for induction of DNA damage, the cellular model, and the phosphoproteomic approach applied, individual drug-regulated p-sites are shared between both studies.…”