PARP1 Inhibition Radiosensitizes Models of Inflammatory Breast Cancer to Ionizing Radiation

Abstract

Sustained locoregional control of disease is a significant issue in patients with inflammatory breast cancer (IBC), with local control rates of 80% or less at 5 years. Given the unsatisfactory outcomes for these patients, there is a clear need for intensification of local therapy, including radiation. Inhibition of the DNA repair protein PARP1 has had little efficacy as a single agent in breast cancer outside of studies restricted to patients with BRCA mutations; however, PARP1 inhibition (PARPi) may lead to the radiosensitization of aggressive tumor types. Thus, this study investigates inhibition of PARP1 as a novel and promising radiosensitization strategy in IBC. In multiple existing IBC models (SUM-149, SUM-190, MDA-IBC-3), PARPi (AZD2281-olaparib and ABT-888-veliparib) had limited single-agent efficacy (IC 50 > 10 mmol/L) in proliferation assays. Despite limited single-agent efficacy, submicromolar concentrations of AZD2281 in combination with RT led to significant radiosensitization (rER 1.12-1.76). This effect was partially dependent on BRCA1 mutational status. Radiosensitization was due, at least in part, to delayed resolution of double strand DNA breaks as measured by multiple assays. Using a SUM-190 xenograft model in vivo, the combination of PARPi and RT significantly delays tumor doubling and tripling times compared with PARPi or RT alone with limited toxicity. This study demonstrates that PARPi improves the effectiveness of radiotherapy in IBC models and provides the preclinical rationale for the opening phase II randomized trial of RT AE PARPi in women with IBC (SWOG 1706, NCT03598257).

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non‐inflammatory breast cancers

“…It is likely that deficient DNA repair contributes to disease progression, as well as to the high TMB observed in IBC and indirectly to its peculiar immune microenvironment (Bertucci et al, 2015;Van Berckelaer et al, 2019;Van Laere et al, 2013). In addition, IBC showed more frequently a HRD and alterations in genes involved in mismatch repair, supporting the ongoing development of PARP inhibitors in IBC as radiosensitizers in phase I-II trials with veliparib (Jagsi et al, 2018) and olaparib (NCT03598257) (Michmerhuizen et al, 2019). This observation warrants a deeper NGS study of IBC, using whole-genome sequencing (WGS) to investigate structural variations.…”

STING enhances cell death through regulation of reactive oxygen species and DNA damage

“…Tumor growth delay was calculated as the time to reach a specified volume (e.g. 400 mm 3 or 600 mm 3 which represent tumor doubling or tripling) in the treated mice relative to untreated mice as has been previously described 65,68 and as such accounts for differences in baseline tumor growth. Data are expressed as a mean ± SEM tumor volume.…”

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

“…Therefore, recent years have seen a surge of interest in the combination of PARPi with other therapies which may revert resistant phenotypes, expanding the indication of these drugs beyond HRR deficient tumors [ 96 , 97 ]. Currently, a number of ongoing clinical trials are assessing, amongst other schemes, the effects of the combination of olaparib and IR on a wide range of tumors, from breast and ovarian to glioblastoma and lung cancers [ 98 , 99 , 100 , 101 , 102 ]. This combination would entail a lower systemic toxicity than combining, for example, PARPi with chemotherapy.…”