elimusertib (BAY 1895344)

HCC1937 and HCC1937-R Talazoparib (TAL) resistant cells were treated with Elimusertib (ELI) alone as ATR inhibitor (ATRi) and ELI and TAL combination. Therefore, the dual targeting of ATR and PARP is a promising modality to reverse PARPi resistance with the downregulation of ATR-Chk1 based DNA damage response. However, further preclinical and clinical investigations should be required to elucidate the underlying molecular mechanisms behind ATRi and PARPi interactions in TNBC cells.

Cisplatin combined with elimusertib was associated with hematologic toxicity requiring significant dose de-escalation. Elimusertib PK was consistent with prior studies. Only modest activity was observed. Further clinical evaluation of elimusertib plus cisplatin is not warranted.

Based on this finding, we showed that combining DS-8201 with either a HER3-targeting antibody (SIBP-03) or an ATR inhibitor (BAY1895344) resulted in significant synergistic antitumor efficacy without substantial toxicity in vitro or in vivo. Overall, this study revealed that the ATR/FoxO1/HER3 pathway plays a critical role in modulating the efficacy of DS-8201, suggesting that combining DS-8201 with ATR or HER3 inhibition represents a promising therapeutic strategy for HER2-positive cancers.

The Polycomb repressive complex EZH2 inhibitor tazemetostat was recently approved for the treatment of SMARCB1-deficient epithelioid sarcomas, based on the functional antagonism between PRC2 and SMARCB1...We leveraged this collateral synthetic lethal dependency to target PGBD5-dependent DNA damage by inhibition of ATR, but not CHK1, using the ATR inhibitor elimusertib. Consequently, combined EZH2 and ATR inhibition improved therapeutic responses in diverse patient-derived epithelioid and rhabdoid tumors in vivo. This advances a combination epigenetic therapy based on EZH2-PGBD5 synthetic lethal dependency suitable for immediate translation to clinical trials for patients.

Herein, we developed an injectable thermosensitive hydrogel for localized co-delivery of ATRi-BAY-1895344 (BAY) and doxorubicin (DOX), serving as a localized drug depot to minimize systemic toxicity while ensuring sustained tumor-specific drug release exceeding 4 days. This dual-action strategy overcomes chemo-resistance by disabling DDR compensatory mechanisms and prolongs tumor suppression through controlled drug release. The hydrogel platform represents a functional innovation in localized combination therapy, integrating stimuli-responsive drug delivery with DDR pathway disruption for synergistic efficacy.

There was no association between ATM protein loss or ATM alterations and progression-free survival or overall response. Further studies to define optimal predictive biomarkers for ATR inhibitors as monotherapy and in combination are ongoing.

P1, N=74, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2025 --> Jun 2026

The combination of the PI3K inhibitor copanlisib with elimusertib enhanced EFS-2 compared to monotherapy in 3 of 11 models tested. The combination of elimusertib with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib enhanced antitumor activity compared to single agents in PARP-resistant PDX models. Our study shows that ATR inhibition has antitumor activity, including in models with both intrinsic and acquired PARP inhibitor resistance. Further work is needed to better refine patient selection for ATR-based therapies.

Moreover, cells under high DNA replication stress were sensitive to elimusertib. Further studies and treatment strategies with elimusertib are warranted for cancers with a high replication rate.

Developed a novel immortalized hemangioma-derived endothelial cell (iHemEC) model that replicates key IH features, overcoming limitations of primary cell models. Identified Sunitinib and Everolimus as promising therapeutic candidates with superior efficacy, supported by transcriptome and protein analyses. Revealed distinct drug mechanisms, with Everolimus targeting PI3K/AKT/mTOR and Sunitinib inducing chromosome instability and DNA damage.

These results reveal that BAY 1895344 has potential in treating ATC.

Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 146 clinical inhibitors and observed strong synergy for the ATR kinase inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway, including phosphorylated pS468 of CHEK1, as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.