ETS transcription factors as emerging drug targets in cancer

Hsing, Michael; Wang, Yuzhuo; Rennie, Paul S.; Cox, Michael; Cherkasov, Artem

doi:10.1002/med.21575

Cited by 65 publications

(40 citation statements)

References 102 publications

(230 reference statements)

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“…In order to abolish ETV5 activity, possible approaches include emerging methods to target protein degradation 51 , interference with functional binding partners and drugging key target genes or upstream activators such as MAPK signalling. Recent discoveries in the development of small molecules targeting ETS proteins raise hope 52 . Therefore, focussing on targeting ETV5 activity could serve as a basis for new complementary or synergistic therapies oriented to targeting effectors downstream of ALK.…”

Section: Discussionmentioning

confidence: 99%

The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness

Mus

Lambertz

Claeys

et al. 2020

Sci Rep

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neuroblastoma is an aggressive childhood cancer arising from sympatho-adrenergic neuronal progenitors. the low survival rates for high-risk disease point to an urgent need for novel targeted therapeutic approaches. Detailed molecular characterization of the neuroblastoma genomic landscape indicates that ALK-activating mutations are present in 10% of primary tumours. Together with other mutations causing RAS/MAPK pathway activation, ALK mutations are also enriched in relapsed cases and ALK activation was shown to accelerate MYCN-driven tumour formation through hitherto unknown ALK-driven target genes. to gain further insight into how ALK contributes to neuroblastoma aggressiveness, we searched for known oncogenes in our previously reported ALK-driven gene signature. We identified ETV5, a bona fide oncogene in prostate cancer, as robustly upregulated in neuroblastoma cells harbouring ALK mutations, and show high ETV5 levels downstream of the RAS/MAPK axis. Increased ETV5 expression significantly impacted migration, invasion and colony formation in vitro, and ETV5 knockdown reduced proliferation in a murine xenograft model. We also established a gene signature associated with ETV5 knockdown that correlates with poor patient survival. Taken together, our data highlight ETV5 as an intrinsic component of oncogenic ALK-driven signalling through the MApK axis and propose that ETV5 upregulation in neuroblastoma may contribute to tumour aggressiveness. Neuroblastoma is the most common extracranial solid paediatric tumour, accounting for 15% of all childhood cancer deaths and arises from the developing sympathetic nervous system 1. In patients with high-risk disease, 5-year event-free survival is less than 50% 2 , with survivors often suffering from severe side-effects associated with current intensive multi-modal therapies and relapse after first-line therapy 1. Recent sequencing efforts have established the mutational landscape of primary and relapsed neuroblastoma. Primary neuroblastomas, similar to other embryonic tumours, have a very low mutation burden. The 'anaplastic lymphoma kinase' (ALK) tyrosine kinase receptor is the only target with significant recurrent mutations occurring in up to 10% of sporadic cases

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Section: Discussionmentioning

confidence: 99%

The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness

Mus

Lambertz

Claeys

et al. 2020

Sci Rep

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“…E26 transformation-specific (ETS) are a family of 28 transcription factors, all of which contain a highly conserved ETS domain for DNA binding, and many of which are involved in cancer [99]. ETS TFs are considered as major oncodrivers, linking family members FL1 in Ewing sarcoma, ETS in leukemia [100], and ERG gene fusion in prostate cancer [101].…”

Section: Ets1mentioning

confidence: 99%

Transcription Factors in Cancer Development and Therapy

Vishnoi

Viswakarma

Rana

et al. 2020

Cancers

103

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Cancer is a multi-step process and requires constitutive expression/activation of transcription factors (TFs) for growth and survival. Many of the TFs reported so far are critical for carcinogenesis. These include pro-inflammatory TFs, hypoxia-inducible factors (HIFs), cell proliferation and epithelial–mesenchymal transition (EMT)-controlling TFs, pluripotency TFs upregulated in cancer stem-like cells, and the nuclear receptors (NRs). Some of those, including HIFs, Myc, ETS-1, and β-catenin, are multifunctional and may regulate multiple other TFs involved in various pro-oncogenic events, including proliferation, survival, metabolism, invasion, and metastasis. High expression of some TFs is also correlated with poor prognosis and chemoresistance, constituting a significant challenge in cancer treatment. Considering the pivotal role of TFs in cancer, there is an urgent need to develop strategies targeting them. Targeting TFs, in combination with other chemotherapeutics, could emerge as a better strategy to target cancer. So far, targeting NRs have shown promising results in improving survival. In this review, we provide a comprehensive overview of the TFs that play a central role in cancer progression, which could be potential therapeutic candidates for developing specific inhibitors. Here, we also discuss the efforts made to target some of those TFs, including NRs.

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“…Encouragingly, plenty of small molecule inhibitors targeting ETS proteins such as VPC‐18005, YK‐4‐279 have been developed during the past few years and play a role in cell lines with chromosomal translocation ( 80 ). Notably, BRD32048, a tricyclic compound, can also be applied for ETV1-amplified cell lines.…”

Section: The Therapeutic Promise In Targeting E-twenty-six Factors Inmentioning

confidence: 99%

The E-Twenty-Six Family in Hepatocellular Carcinoma: Moving into the Spotlight

et al. 2021

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Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Although therapeutic strategies have recently advanced, tumor metastasis and drug resistance continue to pose challenges in the treatment of HCC. Therefore, new molecular targets are needed to develop novel therapeutic strategies for this cancer. E-twenty-six (ETS) transcription family has been implicated in human malignancies pathogenesis and progression, including leukemia, Ewing sarcoma, gastrointestinal stromal tumors. Recently, increasing studies have expanded its great potential as functional players in other cancers, including HCC. This review focuses primarily on the key functions and molecular mechanisms of ETS factors in HCC. Elucidating these molecular details may provide novel potential therapeutic strategies for cancers.

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ETS transcription factors as emerging drug targets in cancer

Cited by 65 publications

References 102 publications

The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness

The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness

Transcription Factors in Cancer Development and Therapy

The E-Twenty-Six Family in Hepatocellular Carcinoma: Moving into the Spotlight

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