ALT neuroblastoma chemoresistance due to telomere dysfunction–induced ATM activation is reversible with ATM inhibitor AZD0156

Koneru, Balakrishna; Farooqi, Ahsan; Nguyen, Thinh H.; Chen, Wan Hsi; Hindle, Ashly; Eslinger, Cody; Makena, Monish R.; Burrow, Trevor A.; Wilson, Joanne; Smith, Aaron; Reddy, Venkatesh Pilla; Cadogan, Elaine; Durant, Stephen T.; Reynolds, C. Patrick

doi:10.1126/scitranslmed.abd5750

Cited by 34 publications

(32 citation statements)

References 61 publications

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“…Representative images of ALT+ patients with retained ( 3E, 3F ) and lost ATRX expression are shown ( 3G) and full details are provided in Supplementary Table 1 . Thus, we believe that neither ATRX mutation nor loss of ATRX protein expression should be used as a primary biomarker for ALT in HGAT, aligning with similar reports of ALT in neuroblastoma 43 . Additionally, we show that in the pediatric brain tumor population, ALT can occur independent of somatic ATRX alterations.…”

Section: Resultssupporting

confidence: 85%

“…While our data do not show any difference in clinical survival in patients with HGAT with or without ALT, ALT+ cancers are often treatment resistant cancers and novel therapies are needed for these patients 3 . ALT directed therapy remains an attractive target and may help sensitize ALT cancers to traditional cytotoxic chemotherapy 43 . By validating TelomereHunter with CCA, we have identified a computational tool that with additional verification and approval, may be clinically feasible to identify patients with ALT, which may be important as ALT-directed therapies become available.…”

Section: Discussionmentioning

confidence: 99%

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ALT in Pediatric High-Grade Gliomas Can Occur withoutATRXMutation and is Enriched in Patients with Pathogenic Germline MMR Variants

Stundon

Ijaz

Gaonkar

et al. 2022

Preprint

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Background: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. Methods: We performed c-circle analysis (CCA) on 586 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.8% (n=40/586) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on high-grade astrocytic tumors (HGAT). Finally, we examined whether ALT is associated with recurrent somatic or germline alterations. Results: ALT is common in pediatric HGAT (n=24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ HGAT and in 30% of ALT- HGAT. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. Conclusions: We demonstrate that ATRX is mutated in only a subset of ALT+ HGAT, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with development of ALT in patients with HGAT.

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Section: Resultssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

ALT in Pediatric High-Grade Gliomas Can Occur withoutATRXMutation and is Enriched in Patients with Pathogenic Germline MMR Variants

Stundon

Ijaz

Gaonkar

et al. 2022

Preprint

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“…Furthermore, complete inhibition of a critical DDR kinase would not be reflective of a translational approach in a slowly progressing disease such as ADPKD. To confirm our findings, we inhibited ATM pharmacologically [ 37 ] in the Pkd1 RC/RC mice using a high dose of ATM inhibitor (20 mg/kg) which causes complete reduction of chemoresistance from ATM activity [ 38 ]. The level of ATM protein could not however be determined due to a lack of suitable cross-reacting antibodies and increased background staining [ 6 ].…”

Section: Discussionmentioning

confidence: 75%

Kidney Cyst Lining Epithelial Cells Are Resistant to Low-Dose Cisplatin-Induced DNA Damage in a Preclinical Model of Autosomal Dominant Polycystic Kidney Disease

Saravanabavan

Rangan

2022

IJMS

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Increased DNA damage response (DDR) signaling in kidney cyst-lining epithelial cells (CECs) may provide an opportunity for cell-specific therapeutic targeting in autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that inhibiting ataxia telangiectasia mutated (ATM; a proximal DDR kinase) together with low-dose cisplatin overwhelms the DDR response and leads to selective apoptosis of cyst-lining epithelial cells (CECs). Pkd1RC/RC/Atm+/− mice were treated with either vehicle or a single low-dose cisplatin, and the acute effects on CECs (DNA damage and apoptosis) after 72 h and chronic effects on progression (cyst size, inflammation, fibrosis) after 3 weeks were investigated. At 72 h, cisplatin caused a dose-dependent increase in γH2AX-positive nuclei in both CECs and non-cystic tubules but did not cause selective apoptosis in Pkd1RC/RC/Atm+/− mice. Moreover, the increase in γH2AX-positive nuclei was 1.7-fold lower in CECs compared to non-cystic epithelial cells (p < 0.05). Low-dose cisplatin also did not alter long-term disease progression in Pkd1RC/RC/Atm+/− mice. In vitro, human ADPKD cyst-derived cell lines were also resistant to cisplatin (WT9-12: 61.7 ± 4.6%; WT9-7: 64.8 ± 2.7% cell viability) compared to HK-2 (25.1 ± 4.2%), and 3D cyst growth in MDCK cells was not altered. Finally, combined low-dose cisplatin with AZD0156 (an ATM inhibitor) non-selectively reduced γH2AX in both cystic and non-cystic tubular cells and exacerbated cystic kidney disease. In conclusion, these data suggest that CECs are resistant to DNA damage, and that the combination of cisplatin with ATM inhibitors is not an effective strategy for selectively eliminating kidney cysts in ADPKD.

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“…[55][56][57][58] Targeting these telomerase maintenance mechanism pathways are of great interest. ATR inhibitors and ATM inhibitors have been shown preclinically to have activity in cancer cells with alternative lengthening of telomeres, 59,60 and a trial of the ATR inhibitor elimusertib in patients with relapsed solid tumors recently opened (NCT05071209).…”

Section: Targeting Genomic and Other Vulnerabilitiesmentioning

confidence: 99%

High-Risk and Relapsed Neuroblastoma: Toward More Cures and Better Outcomes

DuBois

Macy

Henderson

2022

American Society of Clinical Oncology Educational Book

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Approximately half of the patients diagnosed with neuroblastoma are classified as having high-risk disease. This group continues to have inadequate cure rates despite multiagent chemotherapy, surgery, high-dose chemotherapy with autologous stem cell rescue, and immunotherapy directed against GD2. We review current efforts to try to improve outcomes in patients with newly diagnosed disease by integrating novel targeted therapies earlier in the course of the disease. We further examine a growing list of options available for patients with relapsed or refractory high-risk disease, with an eye toward graduating successful strategies from a relapsed/refractory setting to the frontline setting. Last, we review efforts to study and potentially mitigate the array of late effects faced by survivors of high-risk neuroblastoma.

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ALT neuroblastoma chemoresistance due to telomere dysfunction–induced ATM activation is reversible with ATM inhibitor AZD0156

Cited by 34 publications

References 61 publications

ALT in Pediatric High-Grade Gliomas Can Occur withoutATRXMutation and is Enriched in Patients with Pathogenic Germline MMR Variants

ALT in Pediatric High-Grade Gliomas Can Occur withoutATRXMutation and is Enriched in Patients with Pathogenic Germline MMR Variants

Kidney Cyst Lining Epithelial Cells Are Resistant to Low-Dose Cisplatin-Induced DNA Damage in a Preclinical Model of Autosomal Dominant Polycystic Kidney Disease

High-Risk and Relapsed Neuroblastoma: Toward More Cures and Better Outcomes

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