IGF2/IGF1R Signaling as a Therapeutic Target in MYB-Positive Adenoid Cystic Carcinomas and Other Fusion Gene-Driven Tumors

Andersson, Mattias K.; Åman, Pierre; Stenman, Göran

doi:10.3390/cells8080913

Cited by 37 publications

(27 citation statements)

References 113 publications

(140 reference statements)

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“…A MYB oncogene fusion, through Akt and mitogenactivated protein kinase (MAPK) signaling pathways, activates the expression of NSR, MET, EGFR, IGF1R, and specifically IGF2. The latter, by autocrine stimulation, controls the expression of MYB-NFIB in ACC cells, increasing proliferation and generating changes in the cell cycle and RNA processing (89)(90)(91). Other MYB-related fusions were described, but at lower frequencies than MYB-NFIB.…”

Section: Myb-nfib Pathwaymentioning

confidence: 99%

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Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease

et al. 2020

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Salivary gland carcinomas (SGCs) account for <5% of head and neck malignant neoplasms, further subcategorized in over 20 histological subtypes. For the most part, treatment for advanced disease is guided by morphology. SGCs in general respond poorly to a wide array of standard chemotherapy, with short durability, and significant toxicity. More recently, next-generation sequencing provided significant input on the molecular characterization of each SGC subtype, not only improving diagnostic differentiation between morphologically similar tumor types but also identifying novel driver pathways that determine tumor biology and may be amenable to targeted therapy. Among the most common histological subtype is adenoid cystic carcinoma, which often harbors a chromosome translocation resulting in an MYB-NFIB oncogene, with various degrees of Myb surface expression. In a smaller subset, NOTCH1 mutations occur, conferring a more aggressive pattern and potential sensitivity to Notch inhibitors. Salivary duct carcinomas may overexpress Her-2 and androgen receptors, with promising clinical outcomes after exposure to targeted therapies approved for other indications. Secretory carcinoma, previously known as mammary analog secretory carcinoma, is distinguished by an ETV6-NTRK3 fusion that can both help differentiate it from its morphologically similar acinar cell carcinoma and make it susceptible to Trk inhibitors. In the present article, we discuss the molecular abnormalities, their impact on tumor biology, and therapeutic opportunities for the most common SGC subtypes and review published and ongoing clinical trials and future perspectives for this rare disease.

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Section: Myb-nfib Pathwaymentioning

confidence: 99%

“…Other MYB-related fusions were described, but at lower frequencies than MYB-NFIB. Myb overexpression can also occur in the absence of detectable genetic alterations, implying that unknown pathways may be involved in its expression at the protein level (89).…”

Section: Myb-nfib Pathwaymentioning

confidence: 99%

Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease

et al. 2020

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“…Recent studies have shown that this translocation results in a fusion of the transcriptional coactivators MAML2 and CRTC1, and MAML2 and CRTC3. MAML2 belongs to a family of Mastermind‐like, nuclear proteins that function as coactivators for Notch receptors, whereas CRTC1 and CRTC3, CREB‐regulated transcription coactivator 1 and 3, belong to a family of highly conserved CREB, cAMP response element‐binding protein, coactivators . Although the finding of t (11;19)(q21‐22;p13) in WT may indicate malignant transformation, clinical studies have demonstrated that patients with fusion‐positive MECs have a significantly better prognosis compared to those with fusion‐negative tumours, thus establishing CRTC1‐MAML2 as a clinically useful biomarker for MECs .…”

Section: Wt Geneticsmentioning

confidence: 99%

Cytopathology and diagnostics of Warthin's tumour

Sučić

Ljubić²,

Perković³

et al. 2020

Cytopathology

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Warthin's tumour (WT) is a benign epithelial salivary tumour, one type of salivary adenoma. Histologically, WT is structured of two components, epithelial tissue that often lines cystic formations and lymphoid tissue in the tumour stroma. FNA is a reliable diagnostic approach in the diagnosis of salivary gland lesions allowing a highly accurate categorization of benign tumour‐like lesions, benign tumours and malignant tumours. In the proposed Milan reporting system of salivary gland lesions, WT is categorized in the IVA group of benign neoplasms. Accurate cytological diagnosis is straightforward when three characteristic components are present: oncocytes, either isolated or associated in clusters, lymphocytes and lymphoid cells and often an inflammatory/necrotic‐like substance. Also, specific features of scintigraphy and radiological imaging contribute to the diagnosis of WT. WT is categorized according to Seifert G. et al in 4 types, depending on the proportions of the epithelial component and lymphoid stroma. Differential cytopathological and pathohistological diagnosis include other salivary gland lesions with lymphoid, oncocytic epithelial and cystic components. In some cases, such as the metaplastic WT variant, there are additional cytopathological and histological diagnostic difficulties. Moreover, bilateral, multicentric or multiple and infrequently seen extra‐salivary localizations of WT are associated with further cytopathological diagnostic difficulties. Also, a rare possibility of malignant transformation of the epithelial or lymphoid component of WT as well as possible association with other primary tumours remains a challenge in accurate cytopathological and histological diagnosis of WT.

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“…Notably, we have previously shown that NFIB which encodes a DNA‐binding transcription factor, is also involved in a gene fusion in salivary gland adenoid cystic carcinomas (ACCs) 23 . The genomic hallmark of these tumors is a t(6;9)(q23;p23) translocation resulting in a MYB‐NFIB gene fusion 23‐25 . The MYB‐NFIB fusion protein consists of the MYB DNA‐binding and transactivation domains fused to the C‐terminal end of NFIB 23 …”

Section: Introductionmentioning

confidence: 99%

Activation of PLAG1 and HMGA2 by gene fusions involving the transcriptional regulator gene NFIB

Afshari

Fehr

Nevado

et al. 2020

Genes Chromosomes & Cancer

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The pleomorphic adenoma (PA), which is the most common salivary gland neoplasm, is a benign tumor characterized by recurrent chromosome rearrangements involving 8q12 and 12q14‐15. We have previously shown that the PLAG1 and HMGA2 oncogenes are the targets of these rearrangements. Here, we have identified previously unrecognized subsets of PAs with ins(9;8)/t(8;9) (n = 5) and ins(9;12)/t(9;12) (n = 8) and breakpoints located in the vicinity of the PLAG1 and HMGA2 loci. RNA‐sequencing and reverse transcriptase (RT)‐PCR analyses of a case with an ins(9;8) revealed a novel NFIB‐PLAG1 fusion in which NFIB exon 4 is linked to PLAG1 exon 3. In contrast to the developmentally regulated PLAG1 gene, NFIB was highly expressed in normal salivary gland, indicating that PLAG1 in this case, as in other variant fusions, is activated by promoter swapping. RT‐PCR analysis of three PAs with t(9;12) revealed two tumors with chimeric transcripts consisting of HMGA2 exon 4 linked to NFIB exons 9 or 3 and one case with a fusion linking HMGA2 exon 3 to NFIB exon 9. The NFIB fusion events resulted in potent activation of PLAG1 and HMGA2. Analysis of the chromatin landscape surrounding NFIB revealed several super‐enhancers in the 5′‐ and 3′‐parts of the NFIB locus and its flanking sequences. These findings indicate that PLAG1 and HMGA2, similar to MYB in adenoid cystic carcinoma, may be activated by enhancer‐hijacking events, in which super‐enhancers in NFIB are translocated upstream of PLAG1 or downstream of HMGA2. Our results further emphasize the role of NFIB as a fusion partner to multiple oncogenes in histopathologically different types of salivary gland tumors.

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IGF2/IGF1R Signaling as a Therapeutic Target in MYB-Positive Adenoid Cystic Carcinomas and Other Fusion Gene-Driven Tumors

Cited by 37 publications

References 113 publications

Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease

Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease

Cytopathology and diagnostics of Warthin's tumour

Activation of PLAG1 and HMGA2 by gene fusions involving the transcriptional regulator gene NFIB

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