The combined effect of USP7 inhibitors and PARP inhibitors in hormone-sensitive and castration-resistant prostate cancer cells

Morra, Francesco; Merolla, Francesco; Napolitano, Valeria; Ilardi, Gennaro; Miro, Caterina; Paladino, Simona; Staibano, Stefania; Cerrato, Aniello; Celetti, Angela

doi:10.18632/oncotarget.16463

Cited by 50 publications

(63 citation statements)

References 58 publications

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“…A serious of inhibitors targeting USP7 was evaluated in vitro and in vivo studies . In which, P5091 was identified as a specific inhibitor of USP7 and showed a promising anti‐cancer effect in several tumors . Here, we found that inactivation of USP7 using P5091 effectively inhibited esophageal cancer cell growth in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 82%

Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA‐mediated apoptosis

Zhang

Sha

et al. 2018

Molecular Carcinogenesis

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Increasing evidence suggests that deubiquitinase USP7 participates in tumor progression by various mechanisms and serves as a potential therapeutic target. However, its expression and role in esophageal cancer remains elusive; the anti-cancer effect by targeting USP7 still needs to be investigated. Here, we reported that USP7 was overexpressed in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent tissues, implying that USP7 was an attractive anticancer target of ESCC. Pharmaceutical or genetic inactivation of USP7 inhibited esophageal cancer cells growth in vitro and in vivo and induced apoptosis. Mechanistically, inhibition of USP7 accumulated poly-ubiquitinated proteins, activated endoplasmic reticulum stress, and increased expression of ATF4, which transcriptionally upregulated expression of NOXA and induced NOXA-mediated apoptosis. These results provide an evidence for clinical investigation of USP7 inhibitors for the treatment of ESCC.

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Section: Discussionmentioning

confidence: 82%

Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA‐mediated apoptosis

Zhang

Sha

et al. 2018

Molecular Carcinogenesis

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“…In line with our results in DuCaP and VCaP (Fig. A), activation of AR by dihydrotestosterone modestly decreased sensitivity to olaparib in LNCaP cells (Morra et al ., ). Despite this, it was found that AR reactivation in androgen‐deprived PCa cell lines, including LNCaP and VCaP, induces a transient increase in dsDNA breaks (Hedayati et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Olaparib is effective in combination with, and as maintenance therapy after, first‐line endocrine therapy in prostate cancer cells

et al. 2018

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A number of prostate cancer (PCa)‐specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration‐resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa, we evaluated a potential use for olaparib in combination with first‐line endocrine treatments, androgen deprivation, and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy. We demonstrate that the LNCaP cell line, possessing multiple aberrations in BRCAness genes, is sensitive to olaparib. Additive effects of olaparib combined with endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG fusion‐positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by olaparib. In consequence, additive effects of olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to olaparib treatment after initial androgen deprivation implicating a possible use of olaparib as maintenance therapy. In sum, our preclinical data recommend olaparib as a synthetic lethal treatment option in combination or sequenced to first‐line endocrine therapy for PCa patients with diagnosed BRCAness.

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“…Moreover, we could recently identify BCL2 overexpression as a marker for the switch to PARP1‐EJ in PCa . Furthermore, reduced levels of the tumor suppressor CCDC6 could also be considered as a potential biomarker for this switch . Currently, we are trying a genome‐wide approach to identify other markers for a repair switch to PARP1‐EJ.…”

Section: Discussionmentioning

confidence: 99%

A functional ex vivo assay to detect PARP1‐EJ repair and radiosensitization by PARP‐inhibitor in prostate cancer

Köcher

Lange

Nordquist

et al. 2019

Intl Journal of Cancer

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Here, we present a functional assay to detect the repair switch to the alternative PARP1‐dependent end joining (PARP1‐EJ) pathway and the associated susceptibility to PARPi‐mediated radiosensitization in freshly collected tumor samples from prostate cancer (PCa) patients, thereby facilitating the selection of patients who should benefit from combined PARPi plus radiotherapy (RT) treatment. Our optimized ex‐vivo approach sustains tumor slices for up to 15 days under culture conditions that maintain proliferation and oxygenation rates, as measured by EdU incorporation and pimonidazole staining, respectively. We present a robust system to analyze DSB repair using, for the first time in an ex vivo tumor slice setting, two DSB‐markers simultaneously i.e. γH2AX and 53BP1. A computer‐based processing method (i) controls variations in DNA content and slicing on the number of repair foci and (ii) measures the PARPi‐mediated enhancement ratio on DSB foci numbers to ensure inter‐patient‐comparability. We validated this approach using a PC3 xenograft model with its previously described repair switch to PARP1‐EJ. More importantly, we show that approximately 30% of the analyzed tumor tissue samples collected from PCa patients display a switch to PARP1‐EJ, as indicated by the enhanced number of residual γH2AX/53BP1 foci exclusively after PARPi+RT. Furthermore, normal prostatic tissues show no repair switch to PARP1‐EJ, indicating that this repair switch and its associated radiosensitizing effect is tumor‐specific. Collectively, we present here a predictive assay for the switch to PARP1‐EJ that enables individualization of anti‐cancer treatment using a combination of RT and radiosensitizing anticancer agents such as PARPi in PCa.

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The combined effect of USP7 inhibitors and PARP inhibitors in hormone-sensitive and castration-resistant prostate cancer cells

Cited by 50 publications

References 58 publications

Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA‐mediated apoptosis

Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA‐mediated apoptosis

Olaparib is effective in combination with, and as maintenance therapy after, first‐line endocrine therapy in prostate cancer cells

A functional ex vivo assay to detect PARP1‐EJ repair and radiosensitization by PARP‐inhibitor in prostate cancer

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