Pharmacologic characterization of fluzoparib, a novel poly(<scp>ADP</scp>‐ribose) polymerase inhibitor undergoing clinical trials

Wang, Lei; Yang, Changyong; Xie, Conghua; Jiang, Jiahua; Gao, Mingzhao; Li, Fu; Li, Yun; Bao, Xubin; Fu, Haoyu; Lou, Liguang

doi:10.1111/cas.13947

Cited by 69 publications

(56 citation statements)

References 26 publications

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“…Given Talazoparib has a significantly greater PARP trapping capacity, it is hypothesized that PARP trapping may be the underlying mechanism by which sensitivity to radiation is induced (Laird et al, 2018). Fluzoparib has been identified as a novel PARPi, in the early stages of preliminary clinical trials (Wang et al, 2019). Fluzoparib has shown promising results in Phase I/II lung cancer clinical trials as a radiosensitizer and in combination with SHR-1316, a PD-L1 inhibitor (Luo et al, 2019).…”

Section: Lung Cancermentioning

confidence: 99%

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Rose

Burgess

O’Byrne

et al. 2020

Front. Cell Dev. Biol.

438

296

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The Poly (ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including the regulation of transcription, apoptosis and the DNA damage response. PARP1 possesses Poly (ADP-ribose) activity and when activated by DNA damage, adds branched PAR chains to facilitate the recruitment of other repair proteins to promote the repair of DNA single-strand breaks. PARP inhibitors (PARPi) were the first approved cancer drugs that specifically targeted the DNA damage response in BRCA1/2 mutated breast and ovarian cancers. Since then, there has been significant advances in our understanding of the mechanisms behind sensitization of tumors to PARP inhibitors and expansion of the use of PARPi to treat several other cancer types. Here, we review the recent advances in the proposed mechanisms of action of PARPi, biomarkers of the tumor response to PARPi, clinical advances in PARPi therapy, including the potential of combination therapies and mechanisms of tumor resistance.

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Section: Lung Cancermentioning

confidence: 99%

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Rose

Burgess

O’Byrne

et al. 2020

Front. Cell Dev. Biol.

438

296

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“…Previous studies reported a G2/M cell cycle arrest after PARPi [34][35][36]. An enhancement of this effect by combination of PARP1 inhibition with irradiation compared to monotherapy was described [37].…”

Section: Discussionmentioning

confidence: 94%

PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation

Jonuscheit

Jost

Gajdošová

et al. 2021

Genes

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(1) Background: Niraparib and Talazoparib are poly (ADP-ribose) polymerase (PARP) 1/2 inhibitors. It is assumed that combining PARP inhibitors with radiotherapy could be beneficial for cancer treatment. In this study, melanoma cells were treated with Niraparib and Talazoparib in combination with ionizing radiation (IR). (2) Methods: The effects of Talazoparib and Niraparib in combination with IR on cell death, clonogenicity and cell cycle arrest were studied in healthy primary fibroblasts and primary melanoma cells. (3) Results: The melanoma cells had a higher PARP1 and PARP2 content than the healthy fibroblasts, and further increased their PARP2 content after the combination therapy. PARP inhibitors both sensitized fibroblasts and melanoma cells to IR. A clear supra-additive effect of KI+IR treatment was detected in two melanoma cell lines analyzing the surviving fraction. The cell death rate increased in the healthy fibroblasts, but to a larger extent in melanoma cells after combined treatment. Finally, a lower percentage of cells in the radiosensitive G2/M phase is present in the healthy fibroblasts compared to the melanoma cells. (4) Conclusions: Both PARP inhibitors sensitize melanoma cells to IR. Healthy tissue seems to be less affected than melanoma cells. However, the great heterogeneity of the results suggests prior testing of the tumor cells in order to personalize the treatment.

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“…Cells were treated with different concentrations of drugs, alone or in combination, as indicated, inhibition rates were determined using sulforhodamine B assays and 50% growth-inhibition concentration (IC 50 ) was calculated using GraphPad Prism software, as described previously. 18 …”

Section: Methodsmentioning

confidence: 99%

YES1 amplification confers trastuzumab–emtansine (T-DM1) resistance in HER2-positive cancer

Wang

et al. 2020

Br J Cancer

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Background Trastuzumab–emtansine (T-DM1), one of the most potent HER2-targeted drugs, shows impressive efficacy in patients with HER2-positive breast cancers. However, resistance inevitably occurs and becomes a critical clinical problem. Methods We modelled the development of acquired resistance by exposing HER2-positive cells to escalating concentrations of T-DM1. Signalling pathways activation was detected by western blotting, gene expression was analysed by qRT-PCR and gene copy numbers were determined by qPCR. The role of Yes on resistance was confirmed by siRNA-mediated knockdown and stable transfection-mediated overexpression. The in vivo effects were tested in xenograft model. Results We found that Yes is overexpressed in T-DM1–resistant cells owing to amplification of chromosome region 18p11.32, where the YES1 gene resides. Yes activated multiple proliferation-related signalling pathways, including EGFR, PI3K and MAPK, and led to cross-resistance to all types of HER2-targeted drugs, including antibody-drug conjugate, antibody and small molecule inhibitor. The outcome of this cross-resistance may be a clinically incurable condition. Importantly, we found that inhibiting Yes with dasatinib sensitised resistant cells in vitro and in vivo. Conclusions Our study revealed that YES1 amplification conferred resistance to HER2-targeted drugs and suggested the potential application of the strategy of combining HER2 and Yes inhibition in the clinic.

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Pharmacologic characterization of fluzoparib, a novel poly(ADP‐ribose) polymerase inhibitor undergoing clinical trials

Cited by 69 publications

References 26 publications

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation

YES1 amplification confers trastuzumab–emtansine (T-DM1) resistance in HER2-positive cancer

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