Deletion of 11q in Neuroblastomas Drives Sensitivity to PARP Inhibition

Menée à l'aide de lignées cellulaires, de xénogreffes et d'échantillons tumoraux congelés après prélèvement sur 412 patients atteints d'un neuroblastome, cette étude montre que les cellules tumorales présentant une délétion dans la région chromosomique 11q sont sensibles aux inhibiteurs de PARP

Résumé en anglais

Purpose : 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.

Experimental Design : 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 in vitro and in vivo models.

Results : We detected that ATM haploinsufficiency and ATM 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 in vivo model, coadministration of temozolomide–olaparib resulted in sustained xenograft regression.

Conclusions : 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.