In vivo and in vitro studies have shown enhanced tumor cell radiosensitivity with the ATRi ceralasertib, elimusertib, and berzosertib, however, the potentiating effect of ATRi on ionizing radiation (IR) through immune-based mechanisms has only been studied with ceralasertib. ATRi elicited differential inflammatory gene induction and dose-dependent unique cytotoxicity profiles in vitro . The immune mediated antitumor effect of ATRi combined with radiation is dose and schedule dependent, and while likely a class effect, may differ between ATRi compounds.

P1, N=39, Recruiting, National Cancer Institute (NCI) | Initiation date: Jun 2026 --> Feb 2027 | Not yet recruiting --> Recruiting

P2, N=63, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial primary completion date: Sep 2025 --> Jun 2026

Exploratory in silico drug-response analyses identified differential predicted responses to entinostat, linsitinib, and VE-822 according to risk status and DUBR expression. This internally validated signature may support exploratory prognostic risk stratification of LSCC within the analyzed TCGA-derived cohort and may highlight DUBR as a candidate molecule for further biological investigation. Further validation in independent external cohorts and dedicated disulfidptosis functional assays is required before these findings can be considered generalizable.

P1, N=27, Not yet recruiting, Washington University School of Medicine

Ceralasertib monotherapy was tolerated; however, responses were limited. Alternative patient selection and combination treatments are being explored.

P1, N=120, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Apr 2026 --> Jan 2027 | Trial primary completion date: Apr 2026 --> Jan 2027

P1/2, N=61, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Mar 2026 --> Sep 2026 | Trial primary completion date: Mar 2026 --> Sep 2026

We demonstrate that inhibitors against ATR (AZD6738), and particularly ATM (AZD1390) and DNA-Pkcs (AZD7648), could significantly decrease clonogenic survival of HNSCC cell lines following PBT at both low and relatively high LET (~2 keV/µm and ~8 keV/µm, respectively). We confirmed that the inhibitors in combination with PBT led to DSB persistence through neutral comet assays and monitoring γH2AX/53BP1 foci. We also show that this strategy can enhance the sensitivity of patient-derived organoids of HNSCC to PBT of both low and high LET, highlighting this as a strategy which should be exploited further.

P1, N=29, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

The combination of RT + ATRi resulted in increased T cell activation compared to the combined treatment with ATMi, respectively. This suggests an advantage of ATRi in comparison to ATMi in combination with RT for induction of beneficial anti-tumor immune responses in HNSCC.

The developed risk model based on three prognostic genes (RRM2, WDR76, and PLEKHH2) exhibited superior predictive accuracy in NSCLC. These results may provide new insights for investigating novel therapeutic targets in NSCLC.