Relevance of ATM Status in Driving Sensitivity to DNA Damage Response Inhibitors in Patient-Derived Xenograft Models

The ataxia-telangiectasia mutated (ATM) gene plays a crucial role in the DNA damage response (DDR) and the repair of double-strand breaks. Loss of ATM function (ATM deficiency) is thought to increase susceptibility to DDR inhibitors (DDRi). To characterize baseline ATM status, whole-exome sequencing (WES), immunohistochemistry (IHC), and Western blotting (WB) were employed across a panel of ATM-mutated patient-derived xenograft (PDX) models representing various tumor types. Antitumor efficacy was evaluated using inhibitors of poly(ADP-ribose)polymerase (PARP, olaparib), ataxia-telangiectasia and rad3-related protein (ATR, AZD6738), and DNA-dependent protein kinase (DNA-PK, AZD7648), both as monotherapies and in combination, to correlate treatment responses with ATM status. Biallelic truncation or frameshift mutations in ATM were associated with complete loss of ATM protein, while monoallelic or missense mutations, such as the recurrent R3008H mutation, did not lead to ATM protein loss as detected by IHC. DDRi responses were variable across the PDX models, with a general trend toward greater efficacy, particularly when combining inhibitors in models with biallelic ATM mutations and protein loss. A PDX model harboring an ATM splice-site mutation (2127T > C), which maintained high baseline ATM expression and KAP1 phosphorylation, responded to all DDRi treatments. These findings underscore the heterogeneity and complexity of ATM deficiency as a therapeutic target, highlighting that current biomarker-based patient selection methods remain imperfect. However, complete ATM loss was the most reliable indicator for DDRi sensitivity.