PARP Inhibition in Cancer: An Update on Clinical Development

Sachdev, Esha; Tabatabai, Roya; Roy, Varun Yadav; Rimel, B.J.; Mita, Monica

doi:10.1007/s11523-019-00680-2

Cited by 140 publications

(99 citation statements)

References 135 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PARP inhibitor (PARPi) treatment prevents the repair of single-stranded DNA breaks and leads to DSBs in cells. BRCA1/2-deficient cells are unable to repair DSBs via the HR pathway, resulting in cell death (103). Consequently, PARP inhibition is considered a promising strategy for the treatment of BRCA1/2-deficient tumors through synthetic lethality.…”

Section: Palb2 and Precision Medicinementioning

confidence: 99%

Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Zhou

Zhang

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

Partner and localizer of BRCA2 (PALB2) is vital for homologous recombination (HR) repair in response to DNA double-strand breaks (DSBs). PALB2 functions as a tumor suppressor and participates in the maintenance of genome integrity. In this review, we summarize the current knowledge of the biological roles of the multifaceted PALB2 protein and of its regulation. Moreover, we describe the link between PALB2 pathogenic variants (PVs) and breast cancer predisposition, aggressive clinicopathological features, and adverse clinical prognosis. We also refer to both the opportunities and challenges that the identification of PALB2 PVs provides in breast cancer genetic counseling and precision medicine.

show abstract

Section: Palb2 and Precision Medicinementioning

confidence: 99%

Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Zhou

Zhang

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Combination therapy uses PARP inhibitors together with radiotherapy, immune therapy, a cytotoxic agent, an angiogenesis blocker, a signaling pathway inhibitor, or a blocker of the DNA damage-response pathway [118]. In these therapeutic strategies, the PARP inhibitor sensitizes the cancer cells for the cytostatic effect of the agent(s) used in combination with it by limiting DNA damage repair.…”

Section: Parp-akt Interactions In Cancer Biologymentioning

confidence: 99%

“…Alternatively, a targeted treatment, such as a signaling pathway inhibitor, could relieve the resistance of tumor cells toward the PARP inhibitor [119]. Up to now, no combination therapy with PARP inhibition was approved by FDA for the clinical practice, although a number of ongoing clinical trials utilize this strategy for various types of cancers [118]. Solid tumors grow in hypoxic condition and undergo metabolic reprograming to provide energy and nutrients for proliferation and survival.…”

Section: Parp-akt Interactions In Cancer Biologymentioning

confidence: 99%

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

Gallyas

Sümegi

Szabó

2020

Cancers

View full text Add to dashboard Cite

Poly(ADP-ribose) polymerase (PARP) inhibitors have recently been introduced in the therapy of several types of cancers not responding to conventional treatments. However, de novo and acquired PARP inhibitor resistance is a significant limiting factor in the clinical therapy, and the underlying mechanisms are not fully understood. Activity of the cytoprotective phosphatidylinositol-3 kinase (PI3K)-Akt pathway is often increased in human cancer that could result from mutation, expressional change, or amplification of upstream growth-related factor signaling elements or elements of the Akt pathway itself. However, PARP-inhibitor-induced activation of the cytoprotective PI3K-Akt pathway is overlooked, although it likely contributes to the development of PARP inhibitor resistance. Here, we briefly summarize the biological role of the PI3K-Akt pathway. Next, we overview the significance of the PARP-Akt interplay in shock, inflammation, cardiac and cerebral reperfusion, and cancer. We also discuss a recently discovered molecular mechanism that explains how PARP inhibition induces Akt activation and may account for apoptosis resistance and mitochondrial protection in oxidative stress and in cancer.

show abstract

“…Moreover, PARP1 is involved in DNA damage repair and its expression is negatively correlated with patient survival rate and prognosis. Given that PARP1 inhibitors (PARPi) are currently used clinically for treating ovarian and metastatic breast cancers [27,28], and PARP inhibition results in the radiosensitisation of HPV/p16-positive HNSCC cells [21,29], we also aimed to determine the combined effects of Syk and PARP inhibition. First, we found that both R406 and the EGFR inhibitor, gefitinib, could induce PARP activation and DNA damage in the three SCC cell lines as indexed by increased PAR formation and γH2AX expression, respectively.…”

Section: Syk and Egfr Regulate Parp1 Activation And Syk Inhibitor Exementioning

confidence: 99%

Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

Huang

Chen

et al. 2020

Cancers

View full text Add to dashboard Cite

Syk is a non-receptor tyrosine kinase involved in the signalling of immunoreceptors and growth factor receptors. Previously, we reported that Syk mediates epidermal growth factor receptor (EGFR) signalling and plays a negative role in the terminal differentiation of keratinocytes. To understand whether Syk is a potential therapeutic target of cancer cells, we further elucidated the role of Syk in disease progression of squamous cell carcinoma (SCC), which is highly associated with EGFR overactivation, and determined the combined effects of Syk and PARP1 inhibitors on SCC viability. We found that pharmacological inhibition of Syk could attenuate the EGF-induced phosphorylation of EGFR, JNK, p38 MAPK, STAT1, and STAT3 in A431, CAL27 and SAS cells. In addition, EGF could induce a Syk-dependent IL-8 gene and protein expression in SCC. Confocal microscopic data demonstrated the ability of the Syk inhibitor to change the subcellular distribution patterns of EGFR after EGF treatment in A431 and SAS cells. Moreover, according to Kaplan-Meier survival curve analysis, higher Syk expression is correlated with poorer patient survival rate and prognosis. Notably, both Syk and EGFR inhibitors could induce PARP activation, and synergistic cytotoxic actions were observed in SCC cells upon the combined treatment of the PARP1 inhibitor olaparib with Syk or the EGFR inhibitor. Collectively, we reported Syk as an important signalling molecule downstream of EGFR that plays crucial roles in SCC development. Combining Syk and PARP inhibition may represent an alternative therapeutic strategy for treating SCC.

show abstract

PARP Inhibition in Cancer: An Update on Clinical Development

Cited by 140 publications

References 135 publications

Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

Contact Info

Product

Resources

About