Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes

Wang, Dong; Li, Chengbo; Zhang, Yuan; Wang, Min; Jiang, Nan; Lin, Xiang; Li, Ting; Roberts, Thomas M.; Zhao, Jean J.; Cheng, Hai‐Ling Margaret; Liu, Pixu

doi:10.1016/j.ygyno.2016.07.092

Cited by 75 publications

(55 citation statements)

References 33 publications

(49 reference statements)

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“…Scale bar, 50 mm. Notably, subsequent studies revealed that the combined inhibition of PI3K/AKT and PARP had a synergistic antitumor effect in several preclinical models of breast, prostate, and ovarian cancer (50)(51)(52)(53). In addition, inhibition of the PI3K/AKT pathway can sensitize PTEN-mutated cancer cells to treatment with a PARP inhibitor (54).…”

Section: Discussionmentioning

confidence: 99%

GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

Pradeep

Villar‐Prados

et al. 2019

Molecular Cancer Therapeutics

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EP-100 is a synthetic lytic peptide that specifically targets the gonadotropin-releasing hormone receptor on cancer cells. To extend the utility of EP-100, we aimed to identify effective combination therapies with EP-100 for ovarian cancer and explore potential mechanisms of this combination. A series of in vitro (MTT assay, immunoblot analysis, reverse-phase protein array, comet assay, and immunofluorescence staining) and in vivo experiments were carried out to determine the biological effects of EP-100 alone and in combination with standard-of-care drugs. EP-100 decreased the viability of ovarian cancer cells and reduced tumor growth in orthotopic mouse models. Of five standard drugs tested (cisplatin, paclitaxel, doxorubicin, topotecan, and olaparib), we found that the combination of EP-100 and olaparib was synergistic in ovarian cancer cell lines. Further experiments revealed that combined treatment of EP-100 and olaparib significantly increased the number of nuclear foci of phosphorylated histone H2AX. In addition, the extent of DNA damage was significantly increased after treatment with EP-100 and olaparib in comet assay. We performed reverse-phase protein array analyses and identified that the PI3K/AKT pathway was inhibited by EP-100, which we validated with in vitro experiments. In vivo experiment using the HeyA8 mouse model demonstrated that mice treated with EP-100 and olaparib had lower tumor weights (0.06 AE 0.13 g) than those treated with a vehicle (1.19 AE 1.09 g), EP-100 alone (0.62 AE 0.78 g), or olaparib alone (0.50 AE 0.63 g). Our findings indicate that combining EP-100 with olaparib is a promising therapeutic strategy for ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

Pradeep

Villar‐Prados

et al. 2019

Molecular Cancer Therapeutics

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“…PARP inhibitors further synergize with inhibitors of the PI3K pathway, as shown in BRCA-proficient TNBC, BRCA1 mutated breast cancer mouse models, PIK3CA mutated ovarian cancer cells, and PTEN mutated endometrial cancer cells Juvekar et al 2012;Wang et al 2016b;Philip et al 2017). A phase I clinical trial revealed synergistic effects between olaparib and the PI3K inhibitor alpelisib in epithelial ovarian cancer, which are most likely based on HR suppression through reduced RAD51 protein levels and RAD51 foci formation (Konstantinopoulos et al 2019).…”

Section: Inhibitors Of Transcription Regulators and Epigenetic Modifiersmentioning

confidence: 98%

PARP and PARG inhibitors in cancer treatment

2020

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Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.

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“…Previous studies reported that BRCA1/2 downregulation might represent a potential indicator of the treatment response of PI3K inhibition in ovarian cancer cells (Wang et al, 2016). We determined the mRNA expression of BRCA1 and BRCA2 by real-time PCR in OVCAR-8 ( Figure 4A), OVCAR-4, HAC-2, and ES-2 cells (Supplementary Figure S2) after AZD compound treatment.…”

Section: Downregulation Of Brca1 and Brca2 By Azd8835 In Ovcar-8 Cellsmentioning

confidence: 99%

Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment

Huang

Chen

et al. 2020

Front. Pharmacol.

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Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy. Herein, we sought to determine the efficacy of phosphoinositide 3-kinase (PI3K)/Akt inhibition using three AZD compounds in a NOD-SCID xenograft mouse model and Akt regulation in a panel of eight ovarian cancer cell lines. Elevated Akt phosphorylation on Ser473 but not on Thr308 in cancerous tissues correlated with short progressionfree survival (PFS), overall survival (OS), and death. AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473. To add, all compounds inhibited the Akt downstream effectors 4E-BP1 and p70S6 kinase. AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment. Only AZD5363 could inhibit COL11A1 mRNA and promoter activity, which are important factors in Akt regulation and chemoresistance in ovarian cancer. By using a mouse xenograft model, AZD8835 and AZD5363, but not AZD8186, caused a significant reduction in tumor formation. AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and pERK protein expression in OVCAR-8 cells with the KRAS mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer.

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Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes

Cited by 75 publications

References 33 publications

GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

PARP and PARG inhibitors in cancer treatment

Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment

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