Targeting the Oncogenic Transcriptional Regulator MYB in Adenoid Cystic Carcinoma by Inhibition of IGF1R/AKT Signaling

Andersson, Mattias K.; Afshari, Maryam Kakay; Andrén, Ywonne; Wick, Michael J.; Stenman, Göran

doi:10.1093/jnci/djx017

Cited by 83 publications

(92 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3a). To confirm that our models are representative of MYBinduced gene expression in ACC, we investigated the association between gene sets derived from MYB/MYB-NFIB overexpressing MCF10A cells compared with a previously published gene expression data set 16 of MYBpositive ACC patient samples ( Supplementary Fig. 2).…”

Section: Myb and Myb-nfib Activate Overlapping Gene Sets Involved In mentioning

confidence: 97%

“…5). To investigate whether ATR is a downstream target of MYB-NFIB in ACC, we analyzed global gene expression data sets with siRNA knockdown of MYB-NFIB in cultured ACC cells 16 . Treatment with MYB siRNA caused a significant decrease in the expression of ATR, suggesting that MYB-NFIB regulates ATR expression in ACC cells (Fig.…”

Section: The Atr Kinase Is a Downstream Target Of Myb And Myb-nfibmentioning

confidence: 99%

“…The concept that MYB is a key driver of ACC is corroborated by whole-exome sequencing and arrayCGH studies of salivary and breast ACCs showing that ACC generally has a stable genome with few other mutations and copy number alterations 9,14,15 . Moreover, recent studies have demonstrated that knockdown of MYB-NFIB expression in cultured, fusionpositive ACC cells results in reduced cell proliferation and decreased ACC spherogenesis under anchorageindependent growth conditions 16 .…”

Section: Introductionmentioning

confidence: 99%

“…Although there is substantial evidence indicating a key role for MYB in ACC pathogenesis, experimental evidence demonstrating that MYB can transform normal human glandular epithelial cells is lacking. Moreover, since ACC cells are exceedingly difficult to grow in culture, preclinical therapeutic target discovery downstream of MYB is severely hampered by the lack of established cell lines 16,17 . Here, we investigate the transforming potential and molecular consequences of MYB and MYB-NFIB overexpression in human mammary epithelial cells and cultured ACC cells.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

ATR is a MYB regulated gene and potential therapeutic target in adenoid cystic carcinoma

et al. 2020

Self Cite

View full text Add to dashboard Cite

Adenoid cystic carcinoma (ACC) is a rare cancer that preferentially occurs in the head and neck, breast, as well as in other sites. It is an aggressive cancer with high rates of recurrence and distant metastasis. Patients with advanced disease are generally incurable due to the lack of effective systemic therapies. Activation of the master transcriptional regulator MYB is the genomic hallmark of ACC. MYB activation occurs through chromosomal translocation, copy number gain or enhancer hijacking, and is the key driving event in the pathogenesis of ACC. However, the functional consequences of alternative mechanisms of MYB activation are still uncertain. Here, we show that overexpression of MYB or MYB-NFIB fusions leads to transformation of human glandular epithelial cells in vitro and results in analogous cellular and molecular consequences. MYB and MYB-NFIB expression led to increased cell proliferation and upregulation of genes involved in cell cycle control, DNA replication, and DNA repair. Notably, we identified the DNAdamage sensor kinase ATR, as a MYB downstream therapeutic target that is overexpressed in primary ACCs and ACC patient-derived xenografts (PDXs). Treatment with the clinical ATR kinase inhibitor VX-970 induced apoptosis in MYBpositive ACC cells and growth inhibition in ACC PDXs. To our knowledge, ATR is the first example of an actionable target downstream of MYB that could be further exploited for therapeutic opportunities in ACC patients. Our findings may also have implications for other types of neoplasms with activation of the MYB oncogene.

show abstract

Section: Myb and Myb-nfib Activate Overlapping Gene Sets Involved In mentioning

confidence: 97%

Section: The Atr Kinase Is a Downstream Target Of Myb And Myb-nfibmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ATR is a MYB regulated gene and potential therapeutic target in adenoid cystic carcinoma

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ten retrospective studies including 658 patients with ACC fulfilled the inclusion criteria and were included in this meta-analysis ( Figure 1). 12,15,17,18,[21][22][23][24][25][26] Three studies without outcome events were excluded, 16,27,28 and one study that investigated the impact of MYB mRNA on prognosis was also excluded. 29 The characteristics of the 10 eligible studies are provided in Table 1.…”

Section: Study Characteristicsmentioning

confidence: 99%

The value of MYB as a prognostic marker for adenoid cystic carcinoma: Meta‐analysis

Liu

Chen²,

Lao

et al. 2019

Head & Neck

View full text Add to dashboard Cite

The aim of this meta‐analysis is to evaluate myeloblastosis (MYB) as a prognostic marker for patients with adenoid cystic carcinoma (ACC) with respect to MYB gene fusion, MYB protein expression, and tumor sites. We comprehensively searched PubMed, Embase, Web of Science, and Cochrane libraries. Ten studies concerning the prognostic comparisons between MYB positivity and negativity were included. The combined positive rates of MYB gene fusion and protein expression were 57.2% and 62.3%, respectively. Overall, no significant prognostic differences were observed between MYB‐positive and MYB‐negative ACCs. When further divided into MYB gene fusion and MYB protein expression subgroups, no significant differences were observed for any survival outcome (overall survival, disease‐free survival, and local control rate). Moreover, MYB also demonstrated no prognostic value in head and neck ACCs. In conclusion, the current studies reveal that MYB is not a good prognostic marker for ACC.

show abstract

The mitotic checkpoint kinase BUB1 is a direct and actionable target of MYB in adenoid cystic carcinoma

Cicirò,

Ragusa,

Nevado

et al. 2023

FEBS Letters

Self Cite

View full text Add to dashboard Cite

Adenoid cystic carcinoma (ACC) is a head and neck cancer that frequently originates in salivary glands, but can also strike other exocrine glands such as the breast. A key molecular alteration found in the majority of ACC cases is MYB gene rearrangements, leading to activation of the oncogenic transcription factor MYB. In this study, we used immortalised breast epithelial cells and an inducible MYB transgene as a model of ACC. Molecular profiling confirmed that MYB‐driven gene expression causes a transition into an ACC‐like state. Using this new cell model, we identified BUB1 as a targetable kinase directly controlled by MYB, whose pharmacological inhibition caused MYB‐dependent synthetic lethality, growth arrest and apoptosis of patient‐derived cells and organoids.

show abstract

Targeting the Oncogenic Transcriptional Regulator MYB in Adenoid Cystic Carcinoma by Inhibition of IGF1R/AKT Signaling

Abstract: MYB-NFIB is an oncogenic driver and a key therapeutic target in ACC that is regulated by AKT-dependent IGF1R signaling. Our studies uncover a new strategy to target an oncogenic transcriptional master regulator and provide new important insights into the biology and treatment of ACC.

Cited by 83 publications

References 41 publications

ATR is a MYB regulated gene and potential therapeutic target in adenoid cystic carcinoma

ATR is a MYB regulated gene and potential therapeutic target in adenoid cystic carcinoma

The value of MYB as a prognostic marker for adenoid cystic carcinoma: Meta‐analysis

The mitotic checkpoint kinase BUB1 is a direct and actionable target of MYB in adenoid cystic carcinoma

Contact Info

Product

Resources

About