Deletion of 11q in Neuroblastomas Drives Sensitivity to PARP Inhibition.

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> 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 <i>in vitro</i> and <i>in vivo</i> models.<b>Results:</b> We detected that <i>ATM</i> haploinsufficiency and <i>ATM</i> 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 <i>in vivo</i> model, coadministration of temozolomide-olaparib resulted in sustained xenograft regression.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 23(22); 6875-87. ©2017 AACR</i>.