Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor

Takagi, Motoki; Yoshida, Misa; Nemoto, Yoshino; Tamaichi, Hiroyuki; Tsuchida, Rika; Seki, Masafumi; Uryu, Kumiko; Hoshino, Naomi; Nishii, Rina; Miyamoto, Satoshi; Saito, Masahiro; Shimizu, Toshiaki; Hanada, Ryoji; Kaneko, Hideo; Fukao, Toshiyuki; Koyama, Takatoshi; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Sato, Yusuke; Fujii, Yoichi; Kataoka, Keisuke; Okuno, Yusuke; Yoshida, Kenichi; Morio, Tomohiro; Oka, Akira; Ohira, Miki; Hayashi, Yasuhide; Nakagawara, Akira; Ogawa, Seishi; Mizutani, Shuki; Takita, Junko

doi:10.1093/jnci/djx062

Cited by 46 publications

(63 citation statements)

References 52 publications

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“…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).…”

Section: Clinical Development Of Ddr Inhibitors Parp Inhibitorsmentioning

confidence: 87%

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

et al. 2020

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Despite intensive multimodal therapy, the survival rate for high risk neuroblastoma (HR-NB) remains <50%. Most cases initially respond to treatment but almost half will subsequently relapse with aggressive treatment resistant disease. Novel treatments exploiting the molecular pathology of NB and/or overcoming resistance to current genotoxic therapies are needed before survival rates can significantly improve. DNA damage response (DDR) defects are frequently observed in HR-NB including allelic deletion and loss of function mutations in key DDR genes, oncogene induced replication stress and cell cycle checkpoint dysfunction. Exploiting defects in the DDR has been a successful treatment strategy in some adult cancers. Here we review the genetic features of HR-NB which lead to DDR defects and the emerging molecular targeting agents to exploit them.

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Section: Clinical Development Of Ddr Inhibitors Parp Inhibitorsmentioning

confidence: 87%

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

et al. 2020

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“…Therefore, to identify patients who can benefit from PARP inhibitors and platinum‐based chemotherapy, direct sequencing of all HR genes would be a more appropriate method. In the era of precision medicine and with the availability of NGS tools, sequencing is a highly rewarding strategy that can be applied to various cancer types …”

Section: Discussionmentioning

confidence: 99%

Using next‐generation sequencing to redefineBRCAnessin triple‐negative breast cancer

et al. 2020

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This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractBRCAness is considered a predictive biomarker to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors. However, recent trials showed that its predictive value was limited in triple-negative breast cancer (TNBC) treated with platinum. Moreover, tumors with mutations of DNA damage response (DDR) genes, such as homologous recombination (HR) genes, could be sensitive to platinum and PARP inhibitors. Thus, we aim to explore the relationship between mutation status of DDR genes and BRCAness in TNBC. We sequenced 56 DDR genes in 120 TNBC and identified BRCAness by array comparative genomic hybridization. The sequencing results showed that 13, 14, and 14 patients had BRCA, non-BRCA HR, and non-HR DDR gene mutations, respectively.Array comparative genomic hybridization revealed that BRCA-mutated and HR genemutated TNBC shared similar BRCAness features, both having higher numbers and longer length of large-scale structural aberration (LSA, >10 Mb) and similar altered chromosomal regions of LSA. These suggested non-BRCA HR gene-mutated TNBC shared similar characteristics with BRCA-mutated TNBC, indicating non-BRCA HR gene-mutated TNBC sensitive to platinum and PARP inhibitors. Among tumors with mutation of non-HR DDR genes, 3 PTEN and 1 MSH6 mutation also contained significant LSAs (BRCAness); however, they had different regions of genomic alteration to BRCA and HR gene-mutated tumors, might explain prior findings that PTEN-and MSH6-mutated cancer cells not sensitive to PARP inhibitors. Therefore, we hypothesize that the heterogeneous genomic background of BRCAness indicates different responsiveness to platinum and PARP inhibitors. Direct sequencing DDR genes in TNBC should be applied to predict their sensitivity toward platinum and PARP inhibitors.

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“…Neuroblastoma derived cell lines with genomic alterations of DNA-damage response associated genes and with BRCA1 or 2 and BARD1 mutations exhibited sensitivity to PARP1 inhibitors (PARP1i) (42). Particularly, neuroblastoma patients with 11q-loss (with ATM haploinsufficiency) define a subgroup of patients with higher sensitivity to PARP1i (43).…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of full-length BARD1 strengthens its role as a tumor suppressor in neuroblastoma

et al. 2020

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BARD1 is associated with the development of high-risk neuroblastoma patients. Particularly, the expression of full length (FL) isoform, FL BARD1, correlates to high-risk neuroblastoma development and its inhibition is sufficient to induce neuroblastoma cells towards a worst phenotype. Here we have investigated the mechanisms of FL BARD1 in neuroblastoma cell lines depleted for FL BARD1 expression. We have shown that FL BARD1 expression protects the cells from spontaneous DNA damage and from damage accumulated after irradiation. We demonstrated a role for FL BARD1 as tumor suppressor to prevent unscheduled mitotic entry of DNA damaged cells and to lead to death cells that have bypassed cell cycle checkpoints. FL BARD1-depleted cells that have survived to checkpoints acquire features of aggressiveness. Overall, our results show that FL BARD1 may defend cells against cancer and prevent malignant transformation of cells.

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Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor

Cited by 46 publications

References 52 publications

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

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

Using next‐generation sequencing to redefineBRCAnessin triple‐negative breast cancer

Functional characterization of full-length BARD1 strengthens its role as a tumor suppressor in neuroblastoma

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