Chk1 inhibition-induced BRCAness synergizes with olaparib in p53-deficient cancer cells

Zhao, Yang; Zhou, Kehui; Xia, Xiangyu; Guo, Yajie; Li, Tao

doi:10.1080/15384101.2022.2111769

Cited by 6 publications

(3 citation statements)

References 37 publications

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“…Intriguingly, recent evidence suggests CHK1 inhibitors may induce BRCAness in cells, thereby sensitizing BRCA wild-type but p53-deficient cells to olaparib. This rationalizes combinations of CHK1 inhibitors and PARPi and hence warrants further investigation in clinical trials [90].…”

Section: Atr/chk1mentioning

confidence: 91%

Evolving DNA repair synthetic lethality targets in cancer

et al. 2022

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DNA damage signaling response and repair (DDR) is a critical defense mechanism against genomic instability. Impaired DNA repair capacity is an important risk factor for cancer development. On the other hand, upregulation of DDR mechanisms is a feature of cancer chemotherapy and radiotherapy resistance. Advances in our understanding of DDR and its complex role in cancer has led to several translational DNA repair targeted investigations culminating in clinically viable precision oncology strategy using PARP inhibitors in breast, ovarian, pancreatic and prostate cancers. Whilst PARP directed synthetic lethality has improved outcomes for many patients, the lack of sustained clinical response and the development of resistance pose significant clinical challenges. Therefore, the search for additional DDR directed drug targets and novel synthetic lethality approaches is highly desirable and is an area of intense pre-clinical and clinical investigation. Here we provide an overview of the mammalian DNA repair pathways and then focus on current state of PARP inhibitors and other emerging DNA repair inhibitors for synthetic lethality in cancer.

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Section: Atr/chk1mentioning

confidence: 91%

Evolving DNA repair synthetic lethality targets in cancer

et al. 2022

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“…Furthermore, comprehensive research conducted by Yang Zhao et al has provided a deeper understanding of how the introduction of a Chk1 inhibitor specifically disrupts homologous recombination-mediated DNA repair in tumor cells that lack inherent resistance to Olaparib. This disruption leads to synthetic lethality in p53-deficient tumors [114]. The primary mechanism behind this effect is attributed to the formation of BRCA1 nuclear foci, which in turn triggers the accumulation of γH2AX, causing DSB, and ultimately resulting in the demise of tumor cells.…”

Section: Combining With Inhibitors Of Dna Damage Repairmentioning

confidence: 99%

Advancements and Obstacles of PARP Inhibitors in Gastric Cancer

Chen,

Hu,

Zhuang

et al. 2023

Cancers

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Gastric cancer (GC) is a common and aggressive cancer of the digestive system, exhibiting high aggressiveness and significant heterogeneity. Despite advancements in improving survival rates over the past few decades, GC continues to carry a worrisome prognosis and notable mortality. As a result, there is an urgent need for novel therapeutic approaches to address GC. Recent targeted sequencing studies have revealed frequent mutations in DNA damage repair (DDR) pathway genes in many GC patients. These mutations lead to an increased reliance on poly (adenosine diphosphate-ribose) polymerase (PARP) for DNA repair, making PARP inhibitors (PARPi) a promising treatment option for GC. This article presents a comprehensive overview of the rationale and development of PARPi, highlighting its progress and challenges in both preclinical and clinical research for treating GC.

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“…However, identification of additional predictive biomarkers is key to determine the treatment options according to the RCC molecular characteristics (132). Drugs that promote HR repair defects in tumor cells (i.e., PI3K inhibitors, cyclin-dependent kinase inhibitors) may increase sensitivity to PARPis (133)(134)(135)(136). As a specific polymerase θ inhibitor, novobiocin is combined with PARPi in treatment of HR-deficient tumors, as well in tumors that have acquired PARPi resistance (137).…”

Section: Future Directionsmentioning

confidence: 99%

Roles of DNA damage repair and precise targeted therapy in renal cancer (Review)

Lai

et al. 2022

Oncol Rep

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The primary subtypes of renal cell carcinoma (RCC) include clear cell, papillary and chromophobe RCC. RCC occurs often due to loss of von Hippel-Lindau (VHL) and accumulation of lipids and glycogen, and RCC cells may exhibit sensitivity to the disruption of normal metabolism or homologous recombination gene defect. Although the application of molecular-targeted drugs (tyrosine kinase inhibitors) and immune checkpoint inhibitors has been recommended for the treatment of advanced RCC, more targets of DNA damage

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Chk1 inhibition-induced BRCAness synergizes with olaparib in p53-deficient cancer cells

Cited by 6 publications

References 37 publications

Evolving DNA repair synthetic lethality targets in cancer

Evolving DNA repair synthetic lethality targets in cancer

Advancements and Obstacles of PARP Inhibitors in Gastric Cancer

Roles of DNA damage repair and precise targeted therapy in renal cancer (Review)

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