This study establishes a synergistic nanotherapeutic strategy to concurrently disrupt the HIF-1α/ATR axis and augment radiodynamic ROS production. By integrating biological pathway inhibition with damage amplification, our strategy effectively overcomes hypoxia-mediated radioresistance, offering a promising and translatable paradigm for enhancing RT outcomes in LUAD.

P3, N=594, Active, not recruiting, AstraZeneca | Trial completion date: Oct 2026 --> Dec 2027

A panel of EC cell lines, including patient-derived models with varying PIK3CA mutation status and platinum sensitivity, was treated with camonsertib (ATR inhibitor) and inavolisib (PI3Kα inhibitor). Our findings establish dual ATR and PI3Kα inhibition as a genotype-informed therapeutic strategy for platinum-resistant EC. PIK3CA mutation status may influence the mode of cell death, supporting its use as a predictive biomarker for patient stratification in future clinical applications.

Inhibiting ATR with BAY1895344 or AZD6738 re-sensitized carboplatin-resistant PDXCs and PDXs to carboplatin, resulting in an increase in DNA damage, and apoptosis. Molecular factors associated with response to the ATR inhibitor/carboplatin combination included low RNA levels of PKMYT1. These results underscore the pivotal roles of ATR and PKMYT1 in mediating resistance to carboplatin in TNBC and support targeting these pathways to overcome carboplatin resistance in this disease.

Ceralasertib plus durvalumab was tolerated and associated with antitumour activity in advanced/metastatic NSCLC and HNSCC.

The formation of DNA double-strand breaks suggests replication fork collapse. Our findings demonstrates that this synthetic targeted therapy, combining a novel liposomal formulation of VitC with an ATR inhibitor, not only enhances DNA damage and the cytotoxic efficacy of ceralasertib but also effectively drives ovarian cancer cells toward cell death.

P3, N=630, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P1/2, N=442, Recruiting, Artios Pharma Ltd | Trial completion date: Dec 2026 --> Dec 2027

P1, N=51, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027 | Trial primary completion date: Mar 2026 --> Mar 2027

The study failed to meet its primary end point of ORR. DDR and homologous recombination repair defects are not consistently actionable with olaparib as monotherapy or in combination with other targeted therapies in a histology-agnostic manner.

These results demonstrate that ATR blockade concurrently enhances the efficacy of genotoxic agents and immune checkpoint inhibitors, thus paving the way for combination therapies in NSCLC.

P1/2, N=357, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Jun 2026