Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia

Knittel, Gero; Rehkämper, Tim; Korovkina, Darya; Liedgens, Paul; Fritz, Christian; Torgovnick, Alessandro; Al-Baldawi, Yussor; Al-Maarri, Mona; Cun, Yupeng; Fedorchenko, Oleg; Riabinska, Arina; Beleggia, Filippo; Nguyen, Phuong-Hien; Wunderlich, Frank; Ortmann, Monika; Montesinos‐Rongen, Manuel; Tausch, Eugen; Stilgenbauer, Stephan; Frenzel, Lukas P.; Herling, Marco; Herling, Carmen D.; Bahlo, Jasmin; Hallek, Michael; Peifer, Martin; Buettner, Reinhard; Persigehl, Thorsten; Reinhardt, Hans Christian

doi:10.1038/s41467-017-00210-6

Cited by 51 publications

(53 citation statements)

References 62 publications

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“…Thus, it has been speculated that it is the HR defect in BRCA1/2 -mutated cancer cells that confers sensitivity to PARP inhibition [73,74]. In line with this concept, further experiments have shown that PARP inhibition is indeed selectively toxic in cancer cells that harbor aberrations in additional HR genes, such as ATM , RAD51 , RAD54 , DSS1 , RPA1 , NBN , ATR , CHEK1 , CHEK2 , FANCD2 , FANCA and FANCC [77,78,79,80,81]. Given that several critical phenotypes that are associated with BRCA1 or BRCA2 deficiency are also detectable in situations where no germline BRCA1/2 mutation can be detected, the term ‘BRCA-ness' has been coined.…”

Section: Targeting Defective Dna Repair Pathways In Familial and Spormentioning

confidence: 57%

“…Moreover, cells and tumors displaying a defective HR pathway appear to be substantially more sensitive to DNA-PKcs and ATR inhibition than their HR-proficient counterparts (fig. 1) [78,80,81,86,87,88,89,92]. Future clinical trials and further preclinical experiments are required to determine the exact role that PARP, DNA-PKcs and ATR inhibitors will assume in the treatment of locally advanced and metastatic PDAC.…”

Section: Clinical Perspectivementioning

confidence: 99%

“…These include, but are probably not limited to, a substantially increased PARP inhibitor sensitivity in HR-defective settings, compared to HR-proficient cells and tumors (fig. 1) [73,74,76,77,78,79,80,81]. First steps of clinical validation have demonstrated the complexity of this disease in BRCA mutation carriers strongly depending on the treatment context [94,95].…”

Section: Clinical Perspectivementioning

confidence: 99%

“…In addition to PARP inhibitors, HR-defective cancer cells were recently shown to display actionable sensitivities against inhibitors to ATR and DNA-PKcs [78,80,81,86,87,88,89]. DNA-PKcs is a central component of the NHEJ pathway [49].…”

Section: Targeting Defective Dna Repair Pathways In Familial and Spormentioning

confidence: 99%

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Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

Schmitt¹,

Feldmann²,

Zander³

et al. 2018

Oncol Res Treat

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Pancreatic cancer is one of the most common causes of cancer-related mortality in the Western world and pancreatic ductal adenocarcinoma (PDAC) is by far the most common pancreatic cancer entity. Locally advanced or metastatic PDAC remains a major clinical challenge, and the prognosis of affected patients is dismal despite substantial research efforts in this area. Recent large-scale genomic analyses of PDAC revealed that KRAS is the most frequently mutated driver gene in this entity. In addition, a relatively large proportion of PDAC patients displays germline variants in genes involved in DNA repair, particularly DNA double-strand repair. Similarly, a sizable fraction of sporadic PDAC cases harbor mutations in genome maintenance genes, such as BRCA1, BRCA2, and ATM. While direct targeting of oncogenic KRAS is currently not possible in the clinical setting, these defects in DNA repair may open new therapeutic avenues. Here, we discuss the potential use of compounds that interfere with DNA repair and genome maintenance mechanisms for the treatment of PDAC. We particularly focus on the genotype-tailored use of compounds, such as PARP inhibitors, as well as ATR- and DNA-protein kinase catalytic subunit (PKcs) inhibitors.

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Section: Targeting Defective Dna Repair Pathways In Familial and Spormentioning

confidence: 57%

Section: Clinical Perspectivementioning

confidence: 99%

Section: Clinical Perspectivementioning

confidence: 99%

Section: Targeting Defective Dna Repair Pathways In Familial and Spormentioning

confidence: 99%

See 2 more Smart Citations

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

Schmitt¹,

Feldmann²,

Zander³

et al. 2018

Oncol Res Treat

Self Cite

View full text Add to dashboard Cite

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“…Knittel et al () demonstrated that the allelic frequency of the TP53 mutation increased, from very low to high, in two CLL patients after fludarabine/cyclophosphamide chemotherapy, suggesting that genotoxic therapy can select this aggressive clone. We underline the importance of avoiding genotoxic therapy in patients bearing TP53 mutation, even at very low mutational load.…”

mentioning

confidence: 99%

Low‐level TP53 mutational load antecedes clonal expansion in chronic lymphocytic leukaemia

et al. 2018

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Expression of “DNA damage response” pathway genes in diffuse large B‐cell lymphoma: The potential for exploiting synthetic lethality

Mansoor,

Kamran,

Rizwan

et al. 2023

Hematological Oncology

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Diffuse large B‐cell lymphoma (DLBCL) and follicular lymphoma (FL) are two of the most prevalent non‐Hodgkin's lymphoma subtypes. Despite advances, treatment resistance and patient relapse remain challenging issues. Our study aimed to scrutinize gene expression distinctions between DLBCL and FL, employing a cohort of 53 DLBCL and 104 FL samples that underwent rigorous screening for genetic anomalies. The NanoString nCounter assay evaluated 730 cancer‐associated genes, focusing on densely tumorous areas in diagnostic samples. Employing the Lymph2Cx method, we determined the cell‐of‐origin (COO) for DLBCL cases. Our meticulous analysis, facilitated by Qlucore Omics Explorer software, unveiled a substantial 37% of genes with significantly differential expression patterns between DLBCL and FL, pointing to nuanced mechanistic disparities. Investigating the impact of FL disease stage and DLBCL COO on gene expression yielded minimal differences, prompting us to direct our attention to consistently divergent genes in DLBCL. Intriguingly, our Gene Set Enrichment Analysis spotlighted 21% of these divergent genes, converging on the DNA damage response (DDR) pathway, vital for cell survival and cancer evolution. Strong positive correlations among most DDR genes were noted, with key genes like BRCA1, FANCA, FEN1, PLOD1, PCNA, and RAD51 distinctly upregulated in DLBCL compared to FL and normal tissue controls. These findings were subsequently validated using RNA seq data on normal controls and DLBCL samples from public databases like The Cancer Genome Atlas (TCGA) and the Genotype‐Tissue Expression (GTEx) databases, enhancing the robustness of our results. Considering the established significance of these DDR genes in solid cancer therapies, our study underscores their potential applicability in DLBCL treatment strategies. In conclusion, our investigation highlights marked gene expression differences between DLBCL and FL, with particular emphasis on the essential DDR pathway. The identification of these DDR genes as potential therapeutic targets encourages further exploration of synthetic lethality‐based approaches for managing DLBCL.

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Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia

Cited by 51 publications

References 62 publications

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

Low‐level TP53 mutational load antecedes clonal expansion in chronic lymphocytic leukaemia

Expression of “DNA damage response” pathway genes in diffuse large B‐cell lymphoma: The potential for exploiting synthetic lethality

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