A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas

Hadjadj, Djihad; Kim, Sukwha; Denecker, Thomas; Driss, Laura Ben; Cadoret, Jean-Charles; Maric, Chrystelle; Baldacci, Giuseppe; Fauchereau, Fabien

doi:10.18632/aging.101356

Cited by 21 publications

(17 citation statements)

References 47 publications

(53 reference statements)

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“…Two recent studies on ACC cell lines already showed the effect of CDK4/6 inhibitors on cell viability. While Fiorentini et al described the effect of palbociclib in dependence with CDK4 and CDK6 mRNA overexpression in NCI-H295R and SW13 cell lines (28), Hadjadj et al investigated palbociclib mainly under consideration of CDK6 expression (31). In our study, we could confirm a concentration-and time-dependent cell viability reduction through palbociclib in NCI-H295R cells and for the first time also in the novel ACC cell line MUC1.…”

Section: Discussionsupporting

confidence: 75%

“…Considering the fact that (1) the CDK4 gene was overexpressed in 62% of ACC samples, (2) CDK4/6 inhibitors such as palbociclib are already approved for breast cancers and under clinical trials for other solid tumors, (3) CDK4 expression correlated with the presence of CN gains at DNA level (2), and (4) palbociclib has been previously tested in ACC cell lines with promising results (28,31), we decided to focus on CDK4 as our best potential drug target for ACC. We also evaluated CDK4 protein expression by immunohistochemistry in a large series of 104 ACC samples and observed a strong correlation with mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

“…In terms of mechanisms, consistent with previous studies reporting the deletion of the RB gene and lack of RB1 in a subset of ACC tumors (14, 46), we found no RB1 protein expression in neither NCI-H295R nor MUC1 cells, similarly to RB negative palbociclib sensitive hepatoma cells. Therefore, we focused our attention on p130/RBL2, a member of the RB-like family, previously reported to be expressed in NCI-H295R cells (28,31,47). Indeed, we could show notable p130/RBL2 expression in NCI-H295R as well as in MUC1 cells and also observed a relative decrease of the p130/RBL2 protein in treated cells indicating that CDK4 inhibition by palbociclib could actually lead to an activation of p130/RBL2, which is involved in cell cycle arrest and senescence (48).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical Carcinoma

et al. 2020

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical Carcinoma

et al. 2020

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“…We demonstrated that CIMP-high carcinomas are chromosomally noisy, frequently bear somatic alterations leading to activation of cell cycle, and exhibit a transcriptional program characterized by increased expression of steroidogenic enzymes, proliferation machinery, and genes coordinating DNA damage-associated processes. Cell cycle and DNA damage-associated genes upregulated in CIMP-high ACC include MELK, AURKB, CDK6, PLK1, and TOP2A which have been successfully targeted in preclinical and translational models of ACC (34)(35)(36)(37)(38), and may even predict clinical responsiveness to combination therapy with etoposide, doxorubicin, cisplatin, and mitotane (39). Although there is currently little data to support a clinical trial evaluating utility of demethylating agents alone in NOTE: Hazard ratios (HR) and 95% confidence intervals (95% CI) were determined by Cox proportional hazards regression using available clinical and molecular data from all tumors in the FMUSPþUM Primary ACC Cohort.…”

Section: Discussionmentioning

confidence: 99%

Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma

Mohan

Lerario

Else

et al. 2019

Clinical Cancer Research

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Purpose: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; however, patients with locoregional disease have variable outcomes. The Cancer Genome Atlas project on ACC (ACC-TCGA) identified that cancers of patients with homogeneously rapidly recurrent or fatal disease bear a unique CpG island hypermethylation phenotype, "CIMP-high." We sought to identify a biomarker that faithfully captures this subgroup. Experimental Design: We analyzed ACC-TCGA data to characterize differentially regulated biological processes, and identify a biomarker that is methylated and silenced exclusively in CIMP-high ACC. In an independent cohort of 114 adrenocortical tumors (80 treatment-naive primary ACC, 22 adrenocortical adenomas, and 12 non-naive/ nonprimary ACC), we evaluated biomarker methylation by a restriction digest/qPCR-based approach, validated by targeted bisulfite sequencing. We evaluated expression of this biomarker and additional prognostic markers by qPCR. Results: We show that CIMP-high ACC is characterized by upregulation of cell cycle and DNA damage response programs, and identify that hypermethylation and silencing of G0S2 distinguishes this subgroup. We confirmed G0S2 hypermethylation and silencing is exclusive to 40% of ACC, and independently predicts shorter disease-free and overall survival (median 14 and 17 months, respectively). Finally, G0S2 methylation combined with validated molecular markers (BUB1B-PINK1) stratifies ACC into three groups, with uniformly favorable, intermediate, and uniformly dismal outcomes. Conclusions: G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal ACC, amenable to targeted assessment using routine molecular diagnostics. Assessing G0S2 methylation is straightforward, feasible for clinical decision-making, and will enable the direction of efficacious adjuvant therapies for patients with aggressive ACC.

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“…These observations support the use of CDK inhibitors for ACC therapeutics. Other recent studies further support that targeting cell cycle-dependent kinases may be therapeutically efficacious in ACC [ 5 , 6 ]. Interestingly, Nilubol et al identified synergism between CDK inhibitors and proteasome inhibitors.…”

mentioning

confidence: 79%

Drug repurposing using high-throughput screening identifies a promising drug combination to treat adrenocortical carcinoma

Lerario

Hammer

2018

Oncotarget

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A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas

Cited by 21 publications

References 47 publications

Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical Carcinoma

Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical Carcinoma

Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma

Drug repurposing using high-throughput screening identifies a promising drug combination to treat adrenocortical carcinoma

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