DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer
Resistance development is a major hurdle in using platinum-based drugs to treat ovarian cancer. One key mechanism driving this resistance is the enhanced DNA damage response in cancer cells. However, the regulation of this response in platinum-resistant ovarian cancer cells remains unclear. Through quantitative high-throughput combinational screening (qHTCS) and RNA sequencing (RNA-seq), we found that the protein dual oxidase maturation factor 1 (DUOXA1) is overexpressed in these resistant cells, leading to increased production of reactive oxygen species (ROS). Elevated ROS levels sustain activation of the ATR-Chk1 pathway, which contributes to cisplatin resistance in ovarian cancer cells. Additionally, our qHTCS analysis identified two Chk1 inhibitors, PF-477736 and AZD7762, that re-sensitize these resistant cells to cisplatin. Inhibiting this pathway through ROS, DUOXA1, ATR, or Chk1 effectively overcomes cisplatin resistance both in vitro and in vivo. Importantly, clinical studies confirm ATR and DUOXA1 activation in ovarian cancer patients, and elevated DUOXA1 or ATR-Chk1 pathway activity correlates with poorer prognosis. Together, our findings uncover a novel mechanism of cisplatin resistance regulation and offer several combination strategies to counteract platinum resistance in ovarian cancer.