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

Liang, Raimunde; Weigand, Isabel; Lippert, Juliane; Kircher, Stefan; Altieri, Barbara; Steinhauer, Sonja; Hantel, Constanze; Rost, S.; Rosenwald, Andreas; Kroiß, Matthias; Fassnacht, Martin; Sbiera, Silviu; Ronchi, Cristina L.

doi:10.3389/fendo.2020.00219

Cited by 31 publications

(35 citation statements)

References 54 publications

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“…However, in this context, it is relevant to mention, that the preclinical screening platform in the field of ACC was inadequate for a long time, as we faced a huge lack of tumor models, with NCI-H295R as the only available cell line of human origin for more than 20 years [17]. In the current study, we have performed an extensive preclinical drug screening and subsequent mechanistical investigation based on classical chemotherapies and innovative targeted agents, using two different adrenocortical cancer cell lines: the classical NCI-H295R cell line and the more recently developed and highly drug-resistant MUC-1 cell line [11,[18][19][20][21][22][23].…”

Section: Discussionmentioning

confidence: 99%

Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment

Bothou

Sharma

et al. 2021

Cancers

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Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.

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Section: Discussionmentioning

confidence: 99%

Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment

Bothou

Sharma

et al. 2021

Cancers

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“…Another study has proven that nilotinib, a selective tyrosine kinase receptor inhibitor, as a cytotoxic drug that combined with ERK inhibitors deserves to be tested as a novel therapy options in ACC patients [ 224 ]. Palbociclib, the first cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved as a cancer therapy, causes a concentration- and time-dependent reduction in ACC cell viability, which was more pronounced in the cells in line with higher CDK4 expression [ 225 ]. Palbociclib in combination with insulin-like growth factor 1/insulin receptor inhibitor linsitinib shows an additive effect [ 225 ].…”

Section: Treatment Optionsmentioning

confidence: 99%

“…Palbociclib, the first cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved as a cancer therapy, causes a concentration- and time-dependent reduction in ACC cell viability, which was more pronounced in the cells in line with higher CDK4 expression [ 225 ]. Palbociclib in combination with insulin-like growth factor 1/insulin receptor inhibitor linsitinib shows an additive effect [ 225 ]. Hedgehog Receptor Patched is expressed in ACC and contributes to doxorubicin efflux and treatment resistance [ 226 ].…”

Section: Treatment Optionsmentioning

confidence: 99%

The Role of Biomarkers in Adrenocortical Carcinoma: A Review of Current Evidence and Future Perspectives

2021

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Adrenocortical carcinoma (ACC) is a rare endocrine malignancy arising from the adrenal cortex often with unexpected biological behavior. It can occur at any age, with two peaks of incidence: in the first and between fifth and seventh decades of life. Although ACC are mostly hormonally active, precursors and metabolites, rather than end products of steroidogenesis are produced by dedifferentiated and immature malignant cells. Distinguishing the etiology of adrenal mass, between benign adenomas, which are quite frequent in general population, and malignant carcinomas with dismal prognosis is often unfeasible. Even after pathohistological analysis, diagnosis of adrenocortical carcinomas is not always straightforward and represents a great challenge for experienced and multidisciplinary expert teams. No single imaging method, hormonal work-up or immunohistochemical labelling can definitively prove the diagnosis of ACC. Over several decades’ great efforts have been made in finding novel reliable and available diagnostic and prognostic factors including steroid metabolome profiling or target gene identification. Despite these achievements, the 5-year mortality rate still accounts for approximately 75% to 90%, ACC is frequently diagnosed in advanced stages and therapeutic options are unfortunately limited. Therefore, imperative is to identify new biological markers that can predict patient prognosis and provide new therapeutic options.

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“…Inactivating mutations in the tumour suppressor TP53 occur in at least another 20% of sporadic ACC [11]. Increased expression of IGF2 (Insulin like growth factor 2) that is found in ~90% of ACC [14][15][16] provided the rationale for a phase III clinical trial with the selective small molecule IGF-1R inhibitor linsitinib but the results were disappointing [17]. Only few patients derive clinical bene t from multi-tyrosine kinase inhibitors that have been clinically tested [18].…”

Section: Introductionmentioning

confidence: 99%

“…The rst paediatric ACC patient-derived xenograft (PDX) model (SJ-ACC3) was reported by Pinto et al [33] and in 2016, Hantel and colleagues successfully developed the rst adult ACC PDX and established a respective cell line, termed MUC-1 [34]. The publication in 2018 of two additional PDXderived ACC cell lines including one from a LS patient [35] increased the number of available human ACC cell lines to four, which now allows comparative studies that better re ect the genetic heterogeneity of ACC [16,[36][37][38].…”

Section: Introductionmentioning

confidence: 99%

A Novel Patient-Derived Cell Line of Adrenocortical Carcinoma Shows a Pathogenic Role of Germline MUTYH Mutation and High Tumour Mutational Burden

Landwehr

Schreiner

Appenzeller

et al. 2020

Preprint

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BackgroundThe response of advanced adrenocortical carcinoma (ACC) to current chemotherapies is unsatisfactory and a limited rate of response to immunotherapy was observed in clinical trials. High tumour mutational burden (TMB) and the presence of a specific DNA signature are characteristic features of tumours with mutations in the gene MUTYH encoding the mutY DNA glycosylase. Both have been shown to potentially predict the response to immunotherapy. High TMB in an ACC cell line model has not been reported yet.MethodsThe JIL-2266 cell line was established from a primary ACC tumour, comprehensively characterised and oxidative damage, caused by a dysfunctional mutY DNA glycosylase, confirmed.ResultsHere, we characterise the novel patient-derived ACC cell line JIL-2266, which is deficient in MUTYH-dependent DNA repair. JIL-2266 cells have a consistent STR marker profile that confirmed congruousness with primary ACC tumour. Cells proliferate with a doubling time of 41±13 hours. Immunohistochemistry revealed positivity for steroidogenic factor-1. Mass spectrometry did not demonstrate significant steroid hormone synthesis. JIL-2266 have hemizygous mutations in the tumour suppressor gene TP53 (c.859G>T:p.E287X) and MUTYH (c.316C>T:p.R106W). Exome sequencing showed 683 single nucleotide variants and 4 insertions/deletions. We found increased oxidative DNA damage in the cell line and the corresponding primary tumour caused by impaired mutY DNA glycosylase function and accumulation of 8-oxoguanine.ConclusionThis model will be valuable as a pre-clinical ACC cell model with high TMB and a tool to study oxidative DNA damage in the adrenal gland.

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

Cited by 31 publications

References 54 publications

Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment

Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment

The Role of Biomarkers in Adrenocortical Carcinoma: A Review of Current Evidence and Future Perspectives

A Novel Patient-Derived Cell Line of Adrenocortical Carcinoma Shows a Pathogenic Role of Germline MUTYH Mutation and High Tumour Mutational Burden

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

Cited by 31 publications

References 54 publications

Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment

Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment

The Role of Biomarkers in Adrenocortical Carcinoma: A Review of Current Evidence and Future Perspectives

A Novel Patient-Derived Cell Line of Adrenocortical Carcinoma Shows a Pathogenic Role of Germline MUTYH&nbsp;Mutation and High Tumour Mutational Burden

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A Novel Patient-Derived Cell Line of Adrenocortical Carcinoma Shows a Pathogenic Role of Germline MUTYH Mutation and High Tumour Mutational Burden