Guiding ATR and PARP inhibitor combinations with chemogenomic screens

Zimmermann, Michal; Bernier, Cynthia; Kaiser, Beatrice; Fournier, Sara; Li, Li; Desjardins, Jessica; Skeldon, Alexander; Rimkunas, Victoria; Veloso, Artur; Young, Jordan T.F.; Roulston, Anne; Zinda, Michael

doi:10.1016/j.celrep.2022.111081

Cited by 24 publications

(20 citation statements)

References 82 publications

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“…BRCA1 deficiency has been implicated in ATR inhibitor response in the past (59,60), suggesting that the improved elimusertib response in the PDX may in part be due to the de novo BRCA1 mutation. Furthermore ERMS_2b acquired a mutation in SETD2 during SoC treatment, which has been shown to enhance sensitivity to ATR inhibition in other tumor entitites (30). Additionally, we examined two EWS PDX derived from the same patient (EWS_3a+b).…”

Section: Resultsmentioning

confidence: 99%

“…Some biomarkers for predicting ATR inhibitor response have been put forward, e.g. ATM loss, TP53 loss, MYC overexpression, CDC25A overexpression, PGBD5 expression and fusion oncoproteins such as EWS-FLI1 and PAX3-FOXO1, which increase sensitivity to ATR inhibitors (22-30) and are currently considered in clinical trial design (NCT04095273, NCT03188965, NCT03682289, NCT04170153, NCT04576091, NCT04535401, NCT04657068, NCT05338346, NCT04616534, NCT04514497, NCT05071209). How most pediatric solid tumor entities may benefit from ATR inhibitor treatment is difficult to predict, as detailed preclinical information is currently missing.…”

Section: Introductionmentioning

confidence: 99%

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Elimusertib outperforms standard of care chemotherapy in preclinical patient-derived pediatric solid tumor models

Pusch

García

et al. 2022

Preprint

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The small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical anti-tumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in >40 cell lines and >30 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailed in vitro and in vivo molecular characterization of the treated models enabled the evaluation of response biomarkers. Pronounced objective response rates were observed for elimusertib monotherapy in PDX, when treated with a regimen currently used in clinical trials. Strikingly, elimusertib outperformed standard of care chemotherapies, particularly in alveolar rhabdomysarcoma PDX. Thus, elimusertib has strong preclinical anti-tumor activity in pediatric solid tumor models, which may translate to clinically meaningful responses in patients.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Elimusertib outperforms standard of care chemotherapy in preclinical patient-derived pediatric solid tumor models

Pusch

García

et al. 2022

Preprint

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“…One obstacle for combination therapy is the enhanced side effects caused by combining two or more drugs. This can be avoided by identifying genetic alterations that enhance susceptibility towards these drugs 48 . Here we report that POLE4 can serve as a target to enhance the sensitivity of cancer cells to the combination of PARPi and ATRi.…”

Section: Discussionmentioning

confidence: 99%

The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity

Mamar,

Fajka-Boja,

Mórocz

et al. 2023

Preprint

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The clinical success of PARP1/2 inhibitors prompts the expansion of their applicability beyond homologous recombination deficiency. Here, we demonstrate that the loss of the accessory subunits of DNA polymerase epsilon, POLE3 and POLE4, sensitizes cells to PARP inhibitors. We show that the sensitivity of POLE4 knockouts is not due to a compromised response to DNA damage or homologous recombination deficiency. Instead, POLE4 deletion generates replication stress with the accumulation of single-stranded DNA gaps upon PARP inhibitor treatment. In POLE4 knockouts, replication stress leads to elevated DNA-PK signaling revealing a role of POLE4 in regulating DNA-PK activation. Moreover, POLE4 knockouts show synergistic sensitivity to the co-inhibition of ATR and PARP. Finally, POLE4 loss enhances the sensitivity of BRCA1-deficient cells to PARP inhibitors and counteracts acquired resistance consecutive to restoration of homologous recombination. Altogether, our findings establish POLE4 as a promising target to improve PARP inhibitor driven therapies and hamper acquired PARP inhibitor resistance.

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“…Whilst ATR/PARP inhibitors have raised some concerns regarding haematological toxicities, sequential dosing regimens could provide a clinical approach to minimise these side effects [ 171 ]. Moreover, current research using CRISPR chemogenomic screening has identified additional synthetic lethal interactions, including RNaseH2, that synergise with ATR/PARP inhibition, thereby providing novel approaches [ 172 ]. It will be interesting to see if the findings from bulk tumour cells are reproducible within the chemoresistant CSC population.…”

Section: Dna Damage Repair In Cscs and Therapeutic Interventionmentioning

confidence: 99%

DNA Repair and Therapeutic Strategies in Cancer Stem Cells

Gillespie

Ward

Davies

2023

Cancers

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First-line cancer treatments successfully eradicate the differentiated tumour mass but are comparatively ineffective against cancer stem cells (CSCs), a self-renewing subpopulation thought to be responsible for tumour initiation, metastasis, heterogeneity, and recurrence. CSCs are thus presented as the principal target for elimination during cancer treatment. However, CSCs are challenging to drug target because of numerous intrinsic and extrinsic mechanisms of drug resistance. One such mechanism that remains relatively understudied is the DNA damage response (DDR). CSCs are presumed to possess properties that enable enhanced DNA repair efficiency relative to their highly proliferative bulk progeny, facilitating improved repair of double-strand breaks induced by radiotherapy and most chemotherapeutics. This can occur through multiple mechanisms, including increased expression and splicing fidelity of DNA repair genes, robust activation of cell cycle checkpoints, and elevated homologous recombination-mediated DNA repair. Herein, we summarise the current knowledge concerning improved genome integrity in non-transformed stem cells and CSCs, discuss therapeutic opportunities within the DDR for re-sensitising CSCs to genotoxic stressors, and consider the challenges posed regarding unbiased identification of novel DDR-directed strategies in CSCs. A better understanding of the DDR mediating chemo/radioresistance mechanisms in CSCs could lead to novel therapeutic approaches, thereby enhancing treatment efficacy in cancer patients.

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Guiding ATR and PARP inhibitor combinations with chemogenomic screens

Cited by 24 publications

References 82 publications

Elimusertib outperforms standard of care chemotherapy in preclinical patient-derived pediatric solid tumor models

Elimusertib outperforms standard of care chemotherapy in preclinical patient-derived pediatric solid tumor models

The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity

DNA Repair and Therapeutic Strategies in Cancer Stem Cells

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