Deletion of 11q in Neuroblastomas Drives Sensitivity to PARP Inhibition

Abstract

Despite advances in multimodal therapy, neuroblastomas with hemizygous deletion in chromosome 11q (20%-30%) undergo consecutive recurrences with poor outcome. We hypothesized that patients with 11q-loss may share a druggable molecular target(s) that can be exploited for a precision medicine strategy to improve treatment outcome. SNP arrays were combined with next-generation sequencing (NGS) to precisely define the deleted region in 17 primary 11q-loss neuroblastomas and identify allelic variants in genes relevant for neuroblastoma etiology. We assessed PARP inhibitor olaparib in combination with other chemotherapy medications using both and models. We detected that haploinsufficiency and allelic variants are common genetic hallmarks of 11q-loss neuroblastomas. On the basis of the distinct DNA repair pathways triggered by ATM and PARP, we postulated that 11q-loss may define a subgroup of neuroblastomas with higher sensitivity to PARP inhibitors. Noteworthy, concomitant treatment with olaparib and DNA alkylating agent temozolomide potently inhibited growth of cell lines harboring 11q-loss. This drug synergism was less potent when temozolomide was exchanged for cisplatin or irinotecan. Intact 11q cells concomitantly treated with ATM inhibitor displayed growth arrest and enhanced apoptosis, revealing a role for ATM in the mechanism that mediates sensitivity to temozolomide-olaparib. Interestingly, functional TP53 is required for efficacy of this treatment. In an model, coadministration of temozolomide-olaparib resulted in sustained xenograft regression. Our findings reveal a potent synergism between temozolomide and olaparib in treatment of neuroblastomas with 11q-loss and provide a rationale for further clinical investigation. .

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

“…PARP inhibitors have been reported to be synthetically lethal in cells with 11q deletions and ATM mutations in lymphoid tumors (129). Recent studies in preclinical models of NB have also shown that 11q loss confers sensitivity to PARP inhibitors (130,131), further supporting the hypothesis that heterozygous loss of ATM and other DDR genes determines sensitivity to PARP inhibition. In addition to 11q, Colicchia et al showed that PARP inhibition enhances replication stress in MYCN amplified cells and leads to increased cell death through mitotic catastrophe as these cells enter S-phase with damaged DNA (132).…”

Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma

“…PARP1 inhibitors are a therapeutic strategy for BRCA1/PARP pathway de-regulation. Notably, neuroblastomas with deletion of 11q might be a therapeutic target for PARP inhibition [49]. PARP1 (an RBP) is also reported as highly expressed in neuroblastoma and is associated with reduced patient survival [30].…”

ATR Inhibition Potentiates PARP Inhibitor Cytotoxicity in High Risk Neuroblastoma Cell Lines by Multiple Mechanisms

“…Preclinical testing of the PARP inhibitor olaparib (Astra Zeneca) in NB shows that PARP inhibition potentiates the cytotoxic effect of a variety of chemotherapy agents and ionising radiation [28][29][30][31]. In addition, NB tumours with MYCN amplification or ATM deficiency have been shown to have increased sensitivity to single agent olaparib treatment [32,33].…”