Poly(ADP-ribose) polymerase inhibition: past, present and future

Curtin, Nicola J.; Szabó, Csaba

doi:10.1038/s41573-020-0076-6

Cited by 342 publications

(323 citation statements)

References 283 publications

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“…By utilizing the tyrosine kinase inhibitors (e.g., gefitinib and erlotinib) or monoclonal antibodies (e.g., cetuximab and trastuzumab), they can inhibit the activities of EGFR/ERBB2 to effectively suppress the tumor cell growth [ 48 , 49 ]. PARP1 is a nuclear enzyme, and plays a significant role in the maintenance of genome integrity, DNA repair and cell death [ 50 , 51 ]. The clinical utility of PARP inhibitors, such as Olaparib, Niraparib, and Rucaparib, have made great progress in targeting several cancer types, including ovarian, breast, and prostate cancer [ 52 , 53 ].…”

Section: Resultsmentioning

confidence: 99%

Proteomic signatures of 16 major types of human cancer reveal universal and cancer-type-specific proteins for the identification of potential therapeutic targets

et al. 2020

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Background Proteomic characterization of cancers is essential for a comprehensive understanding of key molecular aberrations. However, proteomic profiling of a large cohort of cancer tissues is often limited by the conventional approaches. Methods We present a proteomic landscape of 16 major types of human cancer, based on the analysis of 126 treatment-naïve primary tumor tissues, 94 tumor-matched normal adjacent tissues, and 12 normal tissues, using mass spectrometry-based data-independent acquisition approach. Results In our study, a total of 8527 proteins were mapped to brain, head and neck, breast, lung (both small cell and non-small cell lung cancers), esophagus, stomach, pancreas, liver, colon, kidney, bladder, prostate, uterus and ovary cancers, including 2458 tissue-enriched proteins. Our DIA-based proteomic approach has characterized major human cancers and identified universally expressed proteins as well as tissue-type-specific and cancer-type-specific proteins. In addition, 1139 therapeutic targetable proteins and 21 cancer/testis (CT) antigens were observed. Conclusions Our discoveries not only advance our understanding of human cancers, but also have implications for the design of future large-scale cancer proteomic studies to assist the development of diagnostic and/or therapeutic targets in multiple cancers.

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Section: Resultsmentioning

confidence: 99%

Proteomic signatures of 16 major types of human cancer reveal universal and cancer-type-specific proteins for the identification of potential therapeutic targets

et al. 2020

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“…PARPi are drugs that exploit HRD to kill tumor cells based on a concept termed “synthetic lethality.” 40 Different PARPi are now approved for the treatment of ovarian cancer, prostate cancer, breast cancer, and PDAC 41 . The molecular basis for PARPi therapy is reviewed elsewhere in this volume.…”

Section: Therapeutic Consequences Of Hrd In Pancreatic Cancermentioning

confidence: 99%

Poly(ADP‐ribose) polymerase inhibition in pancreatic cancer

Singh

Bailey

Hübschmann

et al. 2021

Genes Chromosomes & Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Recently, the poly(ADP‐ribose) polymerase inhibitor (PARPi) olaparib has been approved for maintenance therapy after successful platinum‐based chemotherapy in patients with germline mutations in BRCA1 and BRCA2. Approval was based on the POLO study that has shown a significant improvement in progression‐free survival for patients with metastatic PDAC after at least 4 months of platinum‐based chemotherapy. Hopefully, this first biomarker‐directed targeted therapy for a relevant subgroup of pancreatic cancer patients is only the beginning of an era of personalized therapy for pancreatic cancer. The potential role for PARPi in improving survival in patients with pancreatic cancer containing somatic tumor mutations has yet to be established. Multiple studies investigating whether PARPi therapy might benefit a larger group of pancreatic cancer patients with homologous recombination repair deficiency and whether combinations with chemotherapy, immunotherapy, or small molecules can improve efficacy are currently underway. We here review the molecular basis for PARPi therapy in PDAC patients and recent developments in clinical studies.

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“…Combining the transcriptomic data from the two model, PARP1 was identified to be the critical gene which actively expressed in embryonic stem cells and residual tumors after Sorafenib treatment, but progressively decreased along hepatic differentiation. PARP inhibitors have promising effects in inducing synthetic lethality in homozygous recombination deficient tumors in the clinic [7]. Our current study suggested that PARP1 was required for HCC tumor lineage plasticity and residual tumor survival potentially through CHD1L, a chromatin remodeling protein frequently amplified in HCC [8,9].…”

Section: Main Textmentioning

confidence: 65%

PARP inhibitor Olaparib overcomes Sorafenib resistance through reshaping the pluripotent transcriptome in hepatocellular carcinoma

Yang

Kong

et al. 2021

Mol Cancer

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Hepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide with very poor prognosis. Resistance to targeted therapeutic drugs such as sorafenib remains one of the major challenges in clinical treatment. In the present study, PARP1 was found to be highly expressed in human embryonic stem cells, but progressively decreased upon specified hepatic differentiation. Reactivation of PARP1 expression was also detected in HCC residual tumors after sorafenib treatment in xenograft mouse model, indicating the potential important roles of PARP1 in stem cell pluripotency and HCC sorafenib treatment resistance. Overexpression of PARP1 was frequently observed in HCC patients, and closely associated with poor clinical outcome. Treatment of Sorafenib induced activation of DNA damage repair signaling, which is highly active and essential for maintenance of stem cell pluripotency in HCC residual tumors. PARP inhibitor Olaparib extensively suppressed the DNA damage repair signaling, and significantly inhibited the global pluripotent transcriptional network. The repression of key pluripotent transcriptional factors and DNA damage repair signaling by Olaparib was mainly through CHD1L-mediated condensation of the chromatin structure at their promotor regions. The global reshaping of the pluripotent transcriptome by Olaparib might reinforce Sorafenib in eliminating HCC residual tumors and enhance therapeutic efficiency.

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Poly(ADP-ribose) polymerase inhibition: past, present and future

Cited by 342 publications

References 283 publications

Proteomic signatures of 16 major types of human cancer reveal universal and cancer-type-specific proteins for the identification of potential therapeutic targets

Proteomic signatures of 16 major types of human cancer reveal universal and cancer-type-specific proteins for the identification of potential therapeutic targets

Poly(ADP‐ribose) polymerase inhibition in pancreatic cancer

PARP inhibitor Olaparib overcomes Sorafenib resistance through reshaping the pluripotent transcriptome in hepatocellular carcinoma

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