Targeting the PI3K/mTOR Pathway Augments CHK1 Inhibitor–Induced Replication Stress and Antitumor Activity in High-Grade Serous Ovarian Cancer

Huang, Tzu Ting; Brill, Ethan; Nair, Jayakumar; Zhang, Xiaohu; Wilson, Kelli; Chen, Lu; Thomas, Craig J.; Lee, Jungmin

doi:10.1158/0008-5472.can-20-1439

Cited by 15 publications

(16 citation statements)

References 59 publications

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“…As such, the PI3K pathway incorporates DNA replication and cell cycle regulation, and PI3K inhibition causes genomic instability and mitotic catastrophe 54. Another report found that the combination of mTOR inhibitor and ATR inhibitor or CHK1 inhibitor increased cytotoxicity by inducing replication stress in PI3K-activated ovarian cancer cells 38,54. Our study found that loss of NRN1 expression by promoter region methylation sensitized EC cells to PI3K inhibitor.Further study demonstrated that PI3K inhibitor synthesized with ATR/CHK1 inhibitors in NRN1 unexpressed EC cells, while there was no synthetic effect in NRN1 expressed cells.…”

supporting

confidence: 56%

“…PI3K inhibition causes genomic instability and mitotic catastrophe, and also increases replication stress and subsequent DNA damage 12,36,37 . In ovarian cancer, compared with monotherapy, combined samotolisib (PI3K/mTOR inhibitor) and prexasertib (CHK1 inhibitor) treatment increased DNA damage, suggesting that PI3K/mTOR inhibitor augmented CHK1 inhibitor‐induced DNA damage 38 . Another study suggests that combined inhibition of mTOR and ATR or Chk1 increased the efficiency in breast cancer, because all these pathways needed an S phase 39 .…”

Section: Resultsmentioning

confidence: 99%

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Methylation of NRN1 is a novel synthetic lethal marker of PI3K‐Akt‐mTOR and ATR inhibitors in esophageal cancer

Gao

Herman

et al. 2021

Cancer Science

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Wnt, PI3K‐Akt‐mTOR, and NF‐κB pathways were reported to be involved in DNA damage repair (DDR). DDR‐deficient cancers become critically dependent on backup DNA repair pathways. Neuritin 1 (NRN1) is reported to be involved in PI3K‐Akt‐mTOR, and its role in DDR remains unclear. Methylation‐specific PCR, siRNA, flow cytometry, esophageal cancer cell lines, and xenograft mouse models were used to examine the role of NRN1 in esophageal cancer. The expression of NRN1 is frequently repressed by promoter region methylation in human esophageal cancer cells. NRN1 was methylated in 50.4% (510/1012) of primary esophageal cancer samples. NRN1 methylation is associated significantly with age (P < .001), tumor size (P < .01), TNM stage (P < .001), differentiation (P < .001) and alcohol consumption (P < .05). We found that NRN1 methylation is an independent prognostic factor for poor 5‐y overall survival (P < .001). NRN1 inhibits colony formation, cell proliferation, migration, and invasion, and induces apoptosis and G1/S arrest in esophageal cancer cells. NRN1 suppresses KYSE150 and KYSE30 cells xenografts growth in nude mice. PI3K signaling is reported to activate ATR signaling by targeting CHK1, the downstream component of ATR. By analyzing the synthetic efficiency of NVP‐BEZ235 (PI3K inhibitor) and VE‐822 (an ATR inhibitor), we found that the combination of NVP‐BEZ235 and VE‐822 increased cytotoxicity in NRN1 methylated esophageal cancer cells, as well as KYSE150 cell xenografts. In conclusion, NRN1 suppresses esophageal cancer growth both in vitro and in vivo by inhibiting PI3K‐Akt‐mTOR signaling. Methylation of NRN1 is a novel synthetic lethal marker for PI3K‐Akt‐mTOR and ATR inhibitors in human esophageal cancer.

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supporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Methylation of NRN1 is a novel synthetic lethal marker of PI3K‐Akt‐mTOR and ATR inhibitors in esophageal cancer

Gao

Herman

et al. 2021

Cancer Science

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“…Since the PI3K/Akt/mTOR signaling pathway exerts multiple layers of regulation on the repair of DNA DSBs and SSBs, it has been suggested that DDR proteins may represent attractive targets of synthetic lethality with PI3K inhibitors ( 134 ). Indeed, it has been shown that PI3K inhibitors and CHK1 inhibitors combination treatments exhibit remarkably higher cytotoxicity in high-grade serous ovarian carcinoma cells compared with each individual drug alone, with evidence of increased DNA damage, chromosomal breaks, and mitotic catastrophe ( 135 ).…”

Section: Clear Cell Carcinoma Of the Ovarymentioning

confidence: 99%

Targeting DNA Damage Response Pathway in Ovarian Clear Cell Carcinoma

Wong

Cheung

2021

Front. Oncol.

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Ovarian clear cell carcinoma (OCCC) is one of the major types of ovarian cancer and is of higher relative prevalence in Asians. It also shows higher possibility of resistance to cisplatin-based chemotherapy leading to poor prognosis. This may be attributed to the relative lack of mutations and aberrations in homologous recombination-associated genes, which are crucial in DNA damage response (DDR), such as BRCA1, BRCA2, p53, RAD51, and genes in the Fanconi anemia pathway. On the other hand, OCCC is characterized by a number of genetic defects rendering it vulnerable to DDR-targeting therapy, which is emerging as a potent treatment strategy for various cancer types. Mutations of ARID1A, PIK3CA, PTEN, and catenin beta 1 (CTNNB1), as well as overexpression of transcription factor hepatocyte nuclear factor-1β (HNF-1β), and microsatellite instability are common in OCCC. Of particular note is the loss-of-function mutations in ARID1A, which is found in approximately 50% of OCCC. ARID1A is crucial for processing of DNA double-strand break (DSB) and for sustaining DNA damage signaling, rendering ARID1A-deficient cells prone to impaired DNA damage checkpoint regulation and hence sensitive to poly ADP ribose polymerase (PARP) inhibitors. However, while preclinical studies have demonstrated the possibility to exploit DDR deficiency in OCCC for therapeutic purpose, progress in clinical application is lagging. In this review, we will recapitulate the preclinical studies supporting the potential of DDR targeting in OCCC treatment, with emphasis on the role of ARID1A in DDR. Companion diagnostic tests (CDx) for predicting susceptibility to PARP inhibitors are rapidly being developed for solid tumors including ovarian cancers and may readily be applicable on OCCC. The potential of various available DDR-targeting drugs for treating OCCC by drawing analogies with other solid tumors sharing similar genetic characteristics with OCCC will also be discussed.

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“…In soft tissue sarcomas and gastrointestinal stromal tumors, Akt signaling inhibition decreased the RAD51 protein level by regulating protein stability, decreasing the efficacy of homology-mediated repair of DNA DSBs, and ultimately sensitizing tumor cells to doxorubicin ( 43 ). Combining with a PI3K/mTOR pathway inhibitor mitigated the CHK1 inhibitor-induced RAD51-mediated HR repair and augmented replication stress, leading to cell death in high-grade serous ovarian carcinoma ( 44 ). Recently, studies showed that mTOR inhibition promoted adaptive mutagenesis by impairing accurate DNA repair and that the selective mTOR inhibitor PP242 delayed the repair of ionizing radiation-induced DNA DSBs ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage Repair

Gou

Dong

et al. 2022

Front. Oncol.

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BackgroundPoly(ADP-ribose)polymerase (PARP) inhibitors are a class of molecular-targeted cancer drugs. Synthetic lethality is a phenomenon that renders homologous recombination repair defective cells more sensitive to PARP inhibitors. As a component of the cohesin complex, RAD21 regulates DNA damage repair. However, the biological roles of RAD21 in ovarian cancer and their underlying mechanisms remain unclear.MethodsAn immunohistochemical assay was used to validate the expression of RAD21 in ovarian cancer and its correlation with prognosis. The effects of RAD21 were evaluated through Cell Counting Kit-8 (CCK8), wound-healing, and invasion assays in vitro and the tumor growth in vivo. Furthermore, CCK8 assay and immunofluorescence assay were used to detect the effect of RAD21 on cell sensitivity to PARP inhibitors and their mechanism. The pathway changes were detected by Western blotting.ResultsRAD21 was markedly upregulated in ovarian cancer samples. High RAD21 expression was correlated with poor differentiation and poor prognosis in patients with ovarian cancer. Functionally, RAD21 overexpression promoted cancer cell proliferation, migration, and invasion. Moreover, RAD21 knockdown increased the sensitivity of ovarian cancer cells to three kinds of PARP inhibitors by affecting DNA damage repair. In vivo experiments indicated that RAD21 promoted tumor growth. Mechanistically, the overexpression of RAD21 led to increased phosphorylation levels of Akt and mTOR. Blocking the Akt/mTOR signaling pathway reversed RAD21 overexpression-induced cancer progression and drug resistance.ConclusionsRAD21 can serve as a valuable prognostic marker for ovarian cancer and has the potential as a therapeutic target that can expand the utility of PARP inhibitors.

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Targeting the PI3K/mTOR Pathway Augments CHK1 Inhibitor–Induced Replication Stress and Antitumor Activity in High-Grade Serous Ovarian Cancer

Cited by 15 publications

References 59 publications

Methylation of NRN1 is a novel synthetic lethal marker of PI3K‐Akt‐mTOR and ATR inhibitors in esophageal cancer

Methylation of NRN1 is a novel synthetic lethal marker of PI3K‐Akt‐mTOR and ATR inhibitors in esophageal cancer

Targeting DNA Damage Response Pathway in Ovarian Clear Cell Carcinoma

RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage Repair

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