DNA Repair Inhibitors Potentiate Fractionated Radiotherapy More Than Single-Dose Radiotherapy in Breast Cancer Cells

Abstract

Pharmacological inhibitors of DNA damage response (DDR) proteins, such as the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) kinases and poly (ADP-ribose) polymerase (PARP), have been developed to overcome tumor radioresistance. Despite demonstrating radiosensitization preclinically, they have performed suboptimally in clinical trials, possibly due to an incomplete understanding of the influence of DDR inhibition on ionizing radiation (IR) dose fractionation and sublethal damage repair. Hence, this study aimed to evaluate the radiosensitizing ability under fractionation of ATM inhibitor AZD0156, ATR inhibitor AZD6738 and PARP inhibitor AZD2281 (olaparib), utilizing MDA-MB-231 and MCF-7 human breast cancer cells. Clonogenic assays were performed to assess cell survival and sublethal damage repair after treatment with DDR inhibitors and either single-dose or fractionated IR. Immunofluorescence microscopy was utilized to evaluate DNA double-strand break repair kinetics. Cell cycle distributions were investigated using flow cytometry. All inhibitors showed significant radiosensitization, which was significantly greater following fractionated IR than single-dose IR. They also led to more unrepaired DNA double-strand breaks at 24 h post-IR. This study provides preclinical evidence for the role of AZD0156, AZD6738 and olaparib as radiosensitizing agents. Still, it highlights the need to evaluate these drugs in fractionated settings mirroring clinical practice to optimize the trial design.

Telomere-related DNA damage response pathways in cancer therapy: prospective targets

“…Therefore, ensuring that the therapeutic benefits of ATM inhibition outweigh the therapeutic risks are important ( Mukherjee et al, 2018 ; Scully et al, 2019 ; Subecz et al, 2021 ). A Phase I trial has already evaluated the ATM inhibitor AZD0156 as both a monotherapy and in combination with the PARP inhibitors irinotecan and olaparib, which is another cytotoxic agent ( Davis et al, 2022 ; Qin et al, 2022 ; Wong et al, 2022 ).…”

“…Therefore, ATM and ATR inhibitors are also used in cancer therapy to treat patients with ALT-positive cancers. The ATM inhibitor AZD0156 has shown selective toxicity in melanoma cells, neuroblastoma, and preclinical models of colorectal cancer ( Davis et al, 2022 ; Qin et al, 2022 ; Wong et al, 2022 ; Yilmaz et al, 2023 ).…”

Discovery of [1,2,3]Triazolo[4,5-c]quinoline Derivatives as a New Class of Ataxia-Telangiectasia Mutated Kinase Inhibitors

“…AZ31 and AZ32 are ATM inhibitors with 3-quinoline carboxamide and imidazo­[1,2- a ]­pyrazine scaffolds, respectively. AZ31 showed excellent PIKK-family selectivity and pan-kinase selectivity, whereas AZ32 , with enhanced blood–brain barrier (BBB) penetration, is highly efficient in vivo as a radiosensitizer. ,, Compound AZD0156 has an exceptionally high activity and drug-like properties (orally available, a long plasma half-life). − AZD1390 was developed with an improved BBB penetration and similar bioactivity compared to AZD0156 . , AZD1390 is in ongoing phase I clinical trials in combination with radiation therapy for the treatment of patients with primary or recurrent glioblastoma multiforme . Despite these recent advances, it is still necessary to discover more potent ATM inhibitors with new chemical scaffolds.…”