In xenograft models, AZD0156 combined with cisplatin substantially suppressed tumor growth compared to monotherapy, with acceptable tolerability profiles. These findings identify ATM inhibition as a promising strategy to overcome gemcitabine resistance in CCA, particularly in tumors with compromised alt-NHEJ repair capacity, providing a mechanistic rationale for clinical development of this combination therapy.

Finally, the combination of radiotherapy and ACPP-AZD0156 potentiated immune checkpoint inhibitors that resulted in durable tumor control. The therapeutic synergies of ACPP targeted ATM inhibitor to radiosensitize and stimulate anti-tumor immune responses provides a rationale for developing tumor-targeted radiosensitizer drug conjugates that restrict radiosensitization to cancer cells that then engages anti-tumor immune responses to improve cancer patient outcomes.

P1, N=12, Terminated, The Netherlands Cancer Institute | N=30 --> 12 | Trial completion date: Jul 2028 --> Dec 2025 | Recruiting --> Terminated; Endpoint has been reached.

P1, N=39, Recruiting, NYU Langone Health | Not yet recruiting --> Recruiting | Initiation date: Apr 2025 --> Nov 2025

Pretreatment with an ATM inhibitor, KU55933, attenuated APAP-induced hepatocyte damage and resulted in attenuated mothers against decapentaplegic homolog 2/3 (SMAD2/3) signaling with no changes in activated TGFβ1 levels, suggesting that ATM activation modulates TGFβ1 signaling via post-translational mechanisms. APAP was found to promote transforming growth factor beta receptor 2 (TGFβRII) stabilization through activation of phosphorylated casitas B-lineage lymphoma (p-c-cbl) and subsequent neddylation of TGFβRII, which was attenuated by inhibitors of ATM signaling or neddylation machinery. In conclusion, APAP-induced hepatic DNA damage activates an ATM-mediated response that enhances TGFβ1 signaling through stabilization of TGFβRII, and inhibition of ATM consequently reduces APAP-induced hepatic injury.

In vivo experiments confirmed that ATM knockout (ATM KO) or treatment with small-molecule ATM inhibitor KU55933 markedly inhibited osteoclastogenesis of SK-BR-3 cells and the progression of breast cancer bone metastasis. Our results underscore the pivotal role of ATM in regulating NFκB-CCL2 expression and promoting the progression of breast cancer bone metastasis.

Moreover, our analysis identified six subtype-specific drugs, such as KU_55933 and Cyclophosphamide, that were more sensitive to PS1. In conclusion, this study successfully constructed and evaluated a pathway-based molecular subtype and classification model for HCC, thoroughly investigated the biological and multi-omics differences between subtypes. Additionally, the identification of three telomere-associated biomarkers offers guidance and a theoretical basis for personalized treatment and clinical use of drugs for HCC patients.

Here, we studied three approved PARPi, niraparib, olaparib, and rucaparib in three ovarian cancer cell lines and their cisplatin-resistant sublines. Notably, cisplatin resistance was not directly correlated with PARPi resistance, and ATM and ATR inhibitors can increase PARPi activity against cisplatin-sensitive and -resistant ovarian cancer cells. Moreover, we demonstrated for the first time that cell adhesion-mediated resistance can contribute to PARPi resistance, which can also be alleviated by ATR and ATM.

A total of 135 drugs differed in sensitivity between HRG and LRG, including KU.55933...Expression analysis showed that CTSK was significantly downregulated in the BLCA group, while MTERF3, SRC, and CSNK2B were significantly upregulated. In conclusion, CTSK, MTERF3, SRC, and CSNK2B laid the foundation for targeted therapy in the treatment of BLCA.

P2, N=63, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting | N=130 --> 63

Inhibitors such as KU-55933, KU-60019, and AZD1390 have shown the potential to sensitize cancer cells to radiotherapy by impairing DNA repair, thereby enhancing treatment efficacy...Currently, none have gained approval from the FDA or EMA, but six candidates, AZD1390, AZD0156, ZN-B-2262, SYH2051, WSD0628 and M3541 are in clinical trials, often as adjuncts to radiotherapy or in combination with PARP inhibitors. Their safety and effectiveness, however, are still under investigation. This review synthesizes ATM's dual roles and the therapeutic promise of targeting ATM in cancer radiotherapy.

AMA demonstrates significant antitumor activity against NPC by inducing apoptosis, causing cell cycle arrest, and inhibiting HRR. These findings suggest AMA as a promising therapeutic or adjuvant agent for NPC.