Fluzoparib increases radiation sensitivity of non-small cell lung cancer (NSCLC) cells without BRCA1/2 mutation, a novel PARP1 inhibitor undergoing clinical trials

Luo, Juhua; Dai, Xinchi; Hu, Hua; Chen, Jie; Zhao, Lujun; Yang, Changyong; Sun, Jifeng; Zhang, Lianmin; Wang, Qian; Xu, Shilei; Liu, Ningbo; Ying, Guoguang; Wang, Ping

doi:10.1007/s00432-019-03097-6

Cited by 25 publications

(16 citation statements)

References 52 publications

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“…inhibitors ( delayed DDR activity, which breaks the definition that only patients with mutated BRCA1/2 could benefit from PARPi, thus extend the clinical application to more solid tumours and benefit more patients (Luo et al, 2019). Taken together, these data suggest that inhibitors disrupting DNA repair pathways could be promising options in increasing the therapeutic effect of RT.…”

Section: Targeting the Hr Pathwaymentioning

confidence: 92%

“…PARP‐1 is a nuclear enzyme that facilitates BER and DNA strand break repair by modifying key proteins. PARP inhibition causes synthetic lethality in cancer cells with dysfunctional BRCA1/2 , which typically encode for key repair proteins in the HR pathway (Hirai et al, 2016; Luo et al, 2019). As a result of this discovery, PARP1 inhibitors (PARPi) are promising radio‐sensitisers in treating patients with BRCA1/2 ‐mutant tumours.…”

Section: Strategies To Enhance Radio‐sensitivity To Rtmentioning

confidence: 99%

“…Hence, PARPi's could be applicable to a wide therapeutic range of LET radiation therapies, as a radio‐sensitiser through its DNA repair effects. Furthermore, fluzoparib, a novel PARPi, significantly increases the radio‐sensitivity of non‐small cell lung cancer (NSCLC) cells without BRCA1/2 mutations, through underlying mechanisms involved in enhanced apoptosis, G2/M phase arrest, increased IR‐induced DNA lesions, and delayed DDR activity, which breaks the definition that only patients with mutated BRCA1/2 could benefit from PARPi, thus extend the clinical application to more solid tumours and benefit more patients (Luo et al, 2019). Taken together, these data suggest that inhibitors disrupting DNA repair pathways could be promising options in increasing the therapeutic effect of RT.…”

Section: Strategies To Enhance Radio‐sensitivity To Rtmentioning

confidence: 99%

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Harnessing the targeting potential of differential radiobiological effects of photon versus particle radiation for cancer treatment

Zhang

Gan

et al. 2020

Journal Cellular Physiology

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Radiotherapy is one of the major modalities for malignancy treatment. High linear energy transfer (LET) charged-particle beams, like proton and carbon ions, exhibit favourable depth-dose distributions and radiobiological enhancement over conventional low-LET photon irradiation, thereby marking a new era in high precision medicine. Tumour cells have developed multicomponent signal transduction networks known as DNA damage responses (DDRs), which initiate cell-cycle checkpoints and induce double-strand break (DSB) repairs in the nucleus by nonhomologous end joining or homologous recombination pathways, to manage ionising radiation (IR)-induced DNA lesions. DNA damage induction and DSB repair pathways are reportedly dependent on the quality of radiation delivered. In this review, we summarise various types of DNA lesion and DSB repair mechanisms, upon irradiation with low and high-LET radiation, respectively. We also analyse factors influencing DNA repair efficiency. Inhibition of DNA damage repair pathways and dysfunctional cell-cycle checkpoint sensitises tumour cells to IR.

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Section: Targeting the Hr Pathwaymentioning

confidence: 92%

Section: Strategies To Enhance Radio‐sensitivity To Rtmentioning

confidence: 99%

Section: Strategies To Enhance Radio‐sensitivity To Rtmentioning

confidence: 99%

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Harnessing the targeting potential of differential radiobiological effects of photon versus particle radiation for cancer treatment

Zhang

Gan

et al. 2020

Journal Cellular Physiology

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“…Lastly, Fluzoparib (HS10160) was initially identified in 2017 as a novel PARPi (Jhan and Andrechek, 2017). Clinical trials for Fluzoparib commenced in 2019 for the treatment of solid tumors, including ovarian, breast, pancreatic and lung cancer (Han et al, 2019;Luo et al, 2019).…”

Section: Parp Inhibitors -Synthetic Lethalitymentioning

confidence: 99%

“…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.

442

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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