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

Yang, Xiaodong; Kong, Fan-En; Qi, Ling; Lin, Jiaxin; Yan, Qian; Loong, Jane Ho Chun; Xi, Shaoyan; Zhao, Yue; Zhang, Yan; Yuan, Yufeng; Ma, Ning‐Fang; Ma, Stephanie; Guan, Xin‐Yuan; Liu, Ming

doi:10.1186/s12943-021-01315-9

Cited by 51 publications

(27 citation statements)

References 10 publications

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“…As a key repair enzyme, PARP-1 ensures the stability of a tumor cell genome after treatment with DNA damaging chemotherapy agents [ 61 , 62 , 63 ]. PARP-1 is able to promote (directly or indirectly) epigenetic modifications, creating conditions for development of heterogeneity of tumor cells and formation of super-resistant clones in a heterogeneous population [ 64 ]. Another PARP-1-mediated mechanism of drug resistance is a non-lethal autophagy [ 65 , 66 , 67 ].…”

Section: Parp-1 and Oncological Diseasesmentioning

confidence: 99%

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Feofanov

Studitsky

2021

IJMS

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Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in processes of cell cycle regulation, DNA repair, transcription, and replication. Hyperactivity of PARP-1 induced by changes in cell homeostasis promotes development of chronic pathological processes leading to cell death during various metabolic disorders, cardiovascular and neurodegenerative diseases. In contrast, tumor growth is accompanied by a moderate activation of PARP-1 that supports survival of tumor cells due to enhancement of DNA lesion repair and resistance to therapy by DNA damaging agents. That is why PARP inhibitors (PARPi) are promising agents for the therapy of tumor and metabolic diseases. A PARPi family is rapidly growing partly due to natural polyphenols discovered among plant secondary metabolites. This review describes mechanisms of PARP-1 participation in the development of various pathologies, analyzes multiple PARP-dependent pathways of cell degeneration and death, and discusses representative plant polyphenols, which can inhibit PARP-1 directly or suppress unwanted PARP-dependent cellular processes.

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Section: Parp-1 and Oncological Diseasesmentioning

confidence: 99%

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Feofanov

Studitsky

2021

IJMS

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“…A growing number of new approaches pair PARPis with agents targeted at specific molecular alterations in tumors. These molecularly targeted therapies include RTK inhibitors, checkpoint kinase 1/2 (CHK1/2) inhibitors, ATR inhibitors, Wee1 inhibition, PI3K inhibitors, HDAC inhibitors, IGFR inhibitors, Raf inhibitors, MEK inhibitors, or drugs interfering with sex hormone synthesis [ 242 , 243 , 244 , 245 ]. The special edge of PARPis was derived from the discovery of synthetic lethality.…”

Section: Discussionmentioning

confidence: 99%

The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks

Demény

Virág

2021

Cancers

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The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other PARP family members function as mono-ADP-ribosyl transferases. In the last decade, PARP1 has taken center stage in oncology treatments. New PARP inhibitors (PARPi) have been introduced for the targeted treatment of breast cancer 1 or 2 (BRCA1/2)-deficient ovarian and breast cancers, and this novel therapy represents the prototype of the synthetic lethality paradigm. Much less attention has been paid to other PARPs and their potential roles in cancer biology. In this review, we summarize the roles played by all PARP enzyme family members in six intrinsic hallmarks of cancer: uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, reprogrammed energy metabolism, and escape from replicative senescence. In a companion paper, we will discuss the roles of PARP enzymes in cancer hallmarks related to cancer-host interactions, including angiogenesis, invasion and metastasis, evasion of the anticancer immune response, and tumor-promoting inflammation. While PARP1 is clearly involved in all ten cancer hallmarks, an increasing body of evidence supports the role of other PARPs in modifying these cancer hallmarks (e.g., PARP5a and 5b in replicative immortality and PARP2 in cancer metabolism). We also highlight controversies, open questions, and discuss prospects of recent developments related to the wide range of roles played by PARPs in cancer biology. Some of the summarized findings may explain resistance to PARPi therapy or highlight novel biological roles of PARPs that can be therapeutically exploited in novel anticancer treatment paradigms.

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“…Remarkably, embryonic stem cell pluripotency was identified by IPA as a top canonical pathways of both genes mutated in cfDNA of HCC subjects and genes mutated in cfDNA in subjects with advanced fibrosis/cirrhosis, suggesting an essential role in both HCC development and HCC progression. It was previously suggested that DNA damage repair signaling is essential for the maintenance of stem cell pluripotency in HCC [ 65 ] and that p38 MAPK signaling, leading to F-actin reorganization and activation of nuclear factor erythroid 2-related factor 2-mediated oxidative stress response, collectively contribute to enhanced stemness of HCC cells [ 66 ]. EMT was identified as a top canonical pathway only in IPA analysis of HCC mutated genes, confirming its essential role in HCC progression in this study population as well.…”

Section: Discussionmentioning

confidence: 99%

Somatic Mutations in Circulating Cell-Free DNA and Risk for Hepatocellular Carcinoma in Hispanics

Jiao

Sanchez

Thompson

et al. 2021

IJMS

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Hispanics are disproportionally affected by liver fibrosis and hepatocellular carcinoma (HCC). Advanced liver fibrosis is a major risk factor for HCC development. We aimed at identifying somatic mutations in plasma cell-free DNA (cfDNA) of Hispanics with HCC and Hispanics with advanced liver fibrosis but no HCC. Targeted sequencing of over 262 cancer-associated genes identified nonsynonymous mutations in 22 of the 27 HCC patients. Mutations were detected in known HCC-associated genes (e.g., CTNNB1, TP53, NFE2L2, and ARID1A). No difference in cfDNA concentrations was observed between patients with mutations and those without detectable mutations. HCC patients with higher cfDNA concentrations or higher number of mutations had a shorter overall survival (p < 0.001 and p = 0.045). Nonsynonymous mutations were also identified in 17 of the 51 subjects with advanced liver fibrosis. KMT2C was the most commonly mutated gene. Nine genes were mutated in both subjects with advanced fibrosis and HCC patients. Again, no significant difference in cfDNA concentrations was observed between subjects with mutations and those without detectable mutations. Furthermore, higher cfDNA concentrations and higher number of mutations correlated with a death outcome in subjects with advanced fibrosis. In conclusion, cfDNA features are promising non-invasive markers for HCC risk prediction and overall survival.

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

Cited by 51 publications

References 10 publications

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks

Somatic Mutations in Circulating Cell-Free DNA and Risk for Hepatocellular Carcinoma in Hispanics

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