Attenuation of SRC Kinase Activity Augments PARP Inhibitor–mediated Synthetic Lethality in <i>BRCA2</i>-altered Prostate Tumors

Chakraborty, Goutam; Patail, Nabeela Khan; Hirani, Rahim; Nandakumar, Subhiksha; Mazzu, Ying Z.; Yoshikawa, Yuki; Atiq, Mohammad; Jehane, Lina; Stopsack, Konrad H.; Lee, Gwo‐Shu Mary; Abida, Wassim; Morris, Michael J.; Mucci, Lorelei A.; Danila, Daniel C.

doi:10.1158/1078-0432.ccr-20-2483

Cited by 16 publications

(14 citation statements)

References 68 publications

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“…In another study, Chakraborty et al (2021) designed a specific sgRNA to target expression of BRCA2, a key component of DNA damage repair (DDR). Its mutations have a tight association with prostate cancer oncological events [ 196 ]. Variations in DDR pathway genes such as BRCA1 / 2 and ATM occur in 20–25% of men with metastatic castration-resistant prostate cancer (mCRPC) and complicate cancer cell resistance to therapeutic modalities [ 196 ].…”

Section: Crispr/cas9 In Cancersmentioning

confidence: 99%

“…Variations in DDR pathway genes such as BRCA1 / 2 and ATM occur in 20–25% of men with metastatic castration-resistant prostate cancer (mCRPC) and complicate cancer cell resistance to therapeutic modalities [ 196 ]. They found that genetic depletion of BRCA2 established by the CRISPR system caused an antiproliferative effect on prostate cancer cells and enhanced their susceptibility to poly (ADP-ribose) polymerase (PARP) inhibitors, FDA-approved drugs for mCRPC treatment [ 196 ]. Finally, double KO of Akt1 and Akt2 genes potently decreased prostate cancer cell metastasis in vitro and in vivo [ 197 ].…”

Section: Crispr/cas9 In Cancersmentioning

confidence: 99%

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CRISPR/Cas9 application in cancer therapy: a pioneering genome editing tool

et al. 2022

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The progress of genetic engineering in the 1970s brought about a paradigm shift in genome editing technology. The clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) system is a flexible means to target and modify particular DNA sequences in the genome. Several applications of CRISPR/Cas9 are presently being studied in cancer biology and oncology to provide vigorous site-specific gene editing to enhance its biological and clinical uses. CRISPR's flexibility and ease of use have enabled the prompt achievement of almost any preferred alteration with greater efficiency and lower cost than preceding modalities. Also, CRISPR/Cas9 technology has recently been applied to improve the safety and efficacy of chimeric antigen receptor (CAR)-T cell therapies and defeat tumor cell resistance to conventional treatments such as chemotherapy and radiotherapy. The current review summarizes the application of CRISPR/Cas9 in cancer therapy. We also discuss the present obstacles and contemplate future possibilities in this context.

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Section: Crispr/cas9 In Cancersmentioning

confidence: 99%

Section: Crispr/cas9 In Cancersmentioning

confidence: 99%

CRISPR/Cas9 application in cancer therapy: a pioneering genome editing tool

et al. 2022

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“…Milk-derived aflatoxins may thus modify aldo-keto reductase activities, which are in the focus of recent PCa research [552][553][554] . Furthermore, it has been demonstrated in lung cancer cell lines that AFB1 upregulates insulin receptor substrate 2; induces SRC, AKT, and ERK1/2 phosphorylation; and stimulates cancer cell migration, which was inhibited by saracatinib [555] , a kinase inhibitor under investigation in the treatment of PCa [556][557][558][559] . Thus, milk-derived aflatoxins may amplify SRC-and AKT-mediated prostate carcinogenesis.…”

Section: Aflatoxinsmentioning

confidence: 99%

The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

Melnik¹,

John²,

Weiskirchen³

et al. 2022

jtgg

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This review analyzes the potential impact of milk-induced signal transduction on the pathogenesis of prostate cancer (PCa). Articles in PubMed until November 2021 reporting on milk intake and PCa were reviewed. Epidemiological studies identified commercial cow milk consumption as a potential risk factor of PCa. The potential impact of cow milk consumption on the pathogenesis of PCa may already begin during fetal and pubertal prostate growth, critical windows with increased vulnerability. Milk is a promotor of growth and anabolism via activating insulin-like growth factor-1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT/mechanistic target of rapamycin complex 1 (mTORC1) signaling. Estrogens, major steroid hormone components of commercial milk of persistently pregnant dairy cows, activate IGF-1 and mTORC1. Milk-derived signaling synergizes with common driver mutations of the PI3K/AKT/mTORC1 signaling pathway that intersect with androgen receptor, MFG-E8, MAPK, RUNX2, MDM4, TP53, and WNT signaling, respectively. Potential exogenously induced drivers of PCa are milk-induced elevations of growth hormone, IGF-1, MFG-E8, estrogens, phytanic acid, and aflatoxins, as well as milk exosome-derived oncogenic microRNAs including miR-148a, miR-21, and miR-29b. Commercial cow milk intake, especially the consumption of pasteurized milk, which represents the closest replica of native milk, activates PI3K-AKT-mTORC1 signaling via cow milk’s endocrine and epigenetic modes of action. Vulnerable periods for adverse nutrigenomic impacts on prostate health appear to be the fetal and pubertal growth periods, potentially priming the initiation of PCa. Cow milk-mediated overactivation of PI3K-AKT-mTORC1 signaling synergizes with the most common genetic deviations in PCa, promoting PCa initiation, progression, and early recurrence.

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“… 32 , 33 In a previous study, the combined use of Src inhibitors (DAS) and PARP inhibitors (OLA) increased the sensitivity of prostate cancer to OLA, and the inhibition of Src signaling by DAS increased DNA damage in prostate cancer cells, showing favorable therapeutic effects. 34 Moreover, in another study, DAS inhibited cell cycle detection point kinase 1 (Chk1) and induced DNA damage, while OLA inhibited damaged DNA repair. 35 Therefore, the combination of DAS and OLA appears to be a promising treatment for triple negative breast cancer.…”

Section: Introductionmentioning

confidence: 98%

pH-Responsive Hyaluronic Acid Nanoparticles for Enhanced Triple Negative Breast Cancer Therapy

Zeng¹,

Wang²,

Zhang³

et al. 2022

IJN

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Purpose This study emphasized that dasatinib (DAS) and olaparib (OLA) have synergistic effects on triple negative breast cancer, by inducing DNA damage and inhibiting DNA damage repair. However, poor water solubility, short half-life of drugs, and low drug concentration in tumor tissue limit the clinical application. Methods In this research, acid-sensitive ester bonds were used to connect hydrophobic DAS and hydrophilic hyaluronic acid (HA) to form the amphiphilic polymer prodrug HA-DAS, and then OLA was added as the core, the HA-DAS was used as the carrier to form nanomicelles (HDO-NPs) in aqueous. The characterization and drug release of HDO-NPs were studied, and the cytotoxicity, targeting effect, and intracellular transport behavior of HDO-NPs were evaluated in MDA-MB-231. In addition, the pharmacokinetic and therapeutic effect of HDO-NPs were further verified in vivo. Results In vitro characterizations showed that HDO-NPs were spherical with uniform particle size, good stability and anti-dilution ability, and displayed favorable pH-responsive drug release behavior. In addition, the cell experiments showed that HDO-NPs could be effectively taken up by binding to the overexpressed CD44 proteins of MDA-MB-231 cells, resulting in increased intracellular drug concentration. In vivo experiments showed that HDO-NPs can effectively target tumor tissues, have excellent therapeutic effects on tumor, significantly prolong the circulation time of drugs in vivo, and effectively improved the bioavailability of drugs. Conclusion DAS and OLA were designed into micelles, the efficacy of HDO-NPs was higher than that of free drugs. Therefore, HDO-NPs have good application prospects in the treatment of triple negative breast cancer.

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Attenuation of SRC Kinase Activity Augments PARP Inhibitor–mediated Synthetic Lethality in BRCA2-altered Prostate Tumors

Cited by 16 publications

References 68 publications

CRISPR/Cas9 application in cancer therapy: a pioneering genome editing tool

CRISPR/Cas9 application in cancer therapy: a pioneering genome editing tool

The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

pH-Responsive Hyaluronic Acid Nanoparticles for Enhanced Triple Negative Breast Cancer Therapy

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