Impact of <scp>DNA</scp> damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

Slootbeek, Peter H. J.; Duizer, Marleen L.; Doelen, Maarten J. van der; Kloots, Iris S. H.; Kuppen, Malou C.P.; Westgeest, Hans M.; Groot, Carin A. Uyl–de; Naga, Samhita Pamidimarri; Ligtenberg, Marjolijn J. L.; Oort, Inge M. van; Schalken, Jack A.; Kroeze, Leonie I.; Bloemendal, Haiko J.; Mehra, Niven

doi:10.1002/ijc.33306

Cited by 30 publications

(24 citation statements)

References 34 publications

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“…The killing effect of carboplatin is cell apoptosis induced by DNA damage ( 13 ). Therefore, to further explore the effect of PSMD4 on carboplatin sensitivity of EOC cells, flow cytometry was performed.…”

Section: Resultsmentioning

confidence: 99%

Down-regulation of PSMD4 can attenuate autophagy, enhance the accumulation of intracellular ROS, and increase the sensitivity of epithelial ovarian cancer to carboplatin by inhibiting the NF-κB pathway

Li¹,

Zhou²,

Shen³

et al. 2021

Transl Cancer Res TCR

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Background: The incidence of ovarian cancer ranks third among female gynecological cancers in the world, and more than 90% of patients are epithelial ovarian cancer (EOC). Carboplatin is the first-line chemotherapy drug for the treatment of EOC patients. However, patients who are resistant to carboplatin often do not benefit from it. Therefore, finding a key molecule that affects carboplatin sensitivity is expected to enhance the efficacy of carboplatin in EOC treatment. Methods:The human EOC cell line SK-OV-3 and TOV-21G were used in this study. The secondgeneration sequencing technology was used to sequence the transcripts of carboplatin-resistant EOC cells and parental EOC cells. The bioinformatic analysis of the differentially expressed genes was performed by Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.The EOC tissue chip in the Gene Expression Omnibus (GEO) database was also analyzed to screen the target gene. Flow cytometry, Hoechst staining, Western blot, MTS, mitochondrial specific reducing agent (Mito Tempo), and nuclear factor kappa-B (NF-κB) pathway inhibitor (BAY 11-7082) were used to explore the effect of proteasome 26S subunit, non-ATPase 4 (PSMD4) on the autophagy, apoptosis, and reactive oxygen species (ROS) accumulation of carboplatin-resistant EOC cells treated with carboplatin. In vivo, the carboplatin-resistant EOC cell lines treated with PSMD4 knockdown were injected subcutaneously into mice (twelve female BALB/c nude mice) to construct EOC subcutaneous xenograft tumor models.Results: Based on second-generation sequencing technology and bioinformatics analysis, it was found that PSMD4 is the core molecule in the carboplatin resistance regulatory network in EOC, and its expression is up-regulated in EOC carboplatin-resistant tissues and cells. In vitro and in vivo experimental results show that the down-regulated expression of PSMD4 is closely related to the increase in sensitivity of EOC to carboplatin. Mechanically, we found that inhibiting PSMD4 expression may inhibit the activation of the NF-κB pathway, promote carboplatin-induced ROS accumulation in EOC cells, inhibit EOC cell autophagy, and enhance the sensitivity of EOC to carboplatin.

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Section: Resultsmentioning

confidence: 99%

Down-regulation of PSMD4 can attenuate autophagy, enhance the accumulation of intracellular ROS, and increase the sensitivity of epithelial ovarian cancer to carboplatin by inhibiting the NF-κB pathway

Li¹,

Zhou²,

Shen³

et al. 2021

Transl Cancer Res TCR

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“…Men harboring DDR gene mutations had shorter time to CRPC than those with wild type DDR genes (7.3 months vs not reached; p = 0.01). 41 Patients with DDR gene mutations have poor response to ADT alone and combination of ADT with platinum-based chemotherapy 42 or PARP inhibitors 43 would be beneficial for patients with DDR gene mutations.…”

Section: Future Perspectivementioning

confidence: 99%

Treatment Strategies for Metastatic Castration-Sensitive Prostate Cancer: From “All-Comers” to “Personalized” Approach

Harada¹,

Shiota²,

Minato³

et al. 2021

OTT

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“…Cisplatin and carboplatin were shown to exert moderate activity in men with mCRPC (38,39). Retrospective studies revealed that platinum-based chemotherapy was more effective in patients with mCRPC harboring BRCA mutations (Table II) (40)(41)(42)(43). The PSA responses (>50% decline) to platinum were 64%-100% and 17%-36% in BRCA2 mutation carriers and non-carriers, respectively.…”

Section: Are Parp Inhibitors Going To Dramatically Change the Treatment Landscape Of Mcrpc?mentioning

confidence: 99%

Treatment of Metastatic Castration-resistant Prostate Cancer: Are PARP Inhibitors Shifting the Paradigm?

et al. 2021

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Remarkable developments in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have been achieved over the past decade. Although targeting the novel androgen receptor axis and using chemotherapeutic agents have improved survival, mCRPC is still a lethal disease. A better molecular characterization of cancer resulted in the determination of the important role of homologous recombination repair (HRR) genes in cancer development, and poly (ADP-ribose) polymerase (PARP) is one of the most attractive therapeutic targets. Recent clinical studies have demonstrated that PARP inhibitors significantly improve oncological outcomes in patients with mCRPC harboring BRCA mutations, and PARP inhibitors are becoming a standard of care for these patients. However, not only PARP inhibitors, but also chemotherapeutic agents such as platinum agents, taxanes, and radium-223 are active in HRR gene mutation carriers, and platinum sensitivity may predict the efficacy of PARP inhibitors for mCRPC. The combination of PARP inhibitors with other anti-cancer agents may overcome resistance mechanisms against PARP inhibitors and lead to survival benefits. Appropriate treatment sequences and combinations may change the therapeutic landscape of DNA repair deficient mCRPC.

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Impact of DNA damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

Cited by 30 publications

References 34 publications

Down-regulation of PSMD4 can attenuate autophagy, enhance the accumulation of intracellular ROS, and increase the sensitivity of epithelial ovarian cancer to carboplatin by inhibiting the NF-κB pathway

Down-regulation of PSMD4 can attenuate autophagy, enhance the accumulation of intracellular ROS, and increase the sensitivity of epithelial ovarian cancer to carboplatin by inhibiting the NF-κB pathway

Treatment Strategies for Metastatic Castration-Sensitive Prostate Cancer: From “All-Comers” to “Personalized” Approach

Treatment of Metastatic Castration-resistant Prostate Cancer: Are PARP Inhibitors Shifting the Paradigm?

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