Targeting MYC: From understanding its biology to drug discovery

Ross, Julie; Miron, Caitlin E.; Plescia, Jessica; Laplante, Patricia; McBride, Kevin M.; Moitessier, Nicolas; Möröy, Tarik

doi:10.1016/j.ejmech.2020.113137

Cited by 23 publications

(18 citation statements)

References 140 publications

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“…Thyroid carcinomas arising through the effects of MYC overexpression include some papillary carcinomas, follicular carcinomas, poorly differentiated carcinomas, and anaplastic carcinomas [25,26]. In thyroid carcinomas, MYC overexpression develops by various means, including MYC amplification or rearrangements, BRAF v600e mutation interactions, specific long noncoding RNA dysregulation, increased BRD4 protein production, and abnormal TERT expression, among others [25,[27][28][29][30][31]. This patient's tumor may represent another means (e.g., NUTM1 fusion) by which MYC overexpression compels oncogenesis in the neoplastic thyrocyte.…”

Section: Discussionmentioning

confidence: 99%

Thyroid Carcinoma with NSD3::NUTM1 Fusion: a Case with Thyrocyte Differentiation and Colloid Production

et al. 2022

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In this report, we present a high-grade thyroid carcinoma with an NSD3::NUTM1 fusion detected on expanded next-generation sequencing testing. Nuclear protein of the testis (NUT) carcinomas comprise high-grade, aggressive tumors characterized by rearrangements of the NUTM1 gene with various partner genes, most commonly the bromodomain protein genes BRD4 and BRD3. Approximately 10% of NUT carcinomas contain an NSD3::NUTM1 fusion. NUT carcinomas manifest as poorly differentiated or undifferentiated squamous carcinomas, and 33% show areas of mature squamous differentiation. Only exceptionally have NUT carcinomas shown histology discordant from poorly differentiated/undifferentiated squamous carcinoma, and a thyroid NUT carcinoma with histologic thyrocyte differentiation has not been described to date. Our patient’s tumor exhibited mixed cytologic features suggestive of squamoid cells or papillary thyroid carcinoma cells. Overt squamous differentiation was absent, and the tumor produced colloid in poorly formed follicles. Immunophenotypically, the carcinoma was consistent with thyrocyte differentiation with expression of monoclonal PAX8, TTF1, and thyroglobulin (the last predominantly in extracellular colloid). There was zero to < 2% reactivity for proteins typically diffusely expressed in NUT carcinoma: p40, p63, and cytokeratins 5/6. NUT protein expression was equivocal, but fluorescence in situ hybridization confirmed a NUTM1 rearrangement. This exceptional case suggests that NUTM1 fusions may occur in an unknown number of aggressive thyroid carcinomas, possibly with distinctive histologic features but with thyrocyte differentiation. Recognition of this entity potentially has significant prognostic implications. Moreover, thyroid carcinomas with NUTM1 fusions may be amenable to treatment with NUT carcinoma-targeted therapy such as a bromodomain and extraterminal domain protein small molecular inhibitor (BETi).

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Section: Discussionmentioning

confidence: 99%

Thyroid Carcinoma with NSD3::NUTM1 Fusion: a Case with Thyrocyte Differentiation and Colloid Production

et al. 2022

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“…MYC belongs to the family of the basic helix-loop-helix-leucine zipper transcription factor and regulates cell growth, differentiation, and metabolism. Its expression is tightly controlled in normal cells but it is overexpressed in human cancers [ 56 ]. Pancreatic acinar cell carcinomas are distinct aggressive neoplasms in which MYC amplification is frequent (17%) [ 57 ].…”

Section: Altered Pathways Of Pancreatic Cancer and Gemmmentioning

confidence: 99%

Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models

Saiki

Jiang

Ohmuraya

et al. 2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, and the seventh leading cause of cancer-related deaths worldwide. An improved understanding of tumor biology and novel therapeutic discoveries are needed to improve overall survival. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. Advanced GEMMs permit the temporally and spatially controlled manipulation of multiple target genes using a dual-recombinase system or CRISPR/Cas9 gene editing. GEMMs that express fluorescent proteins allow cell lineage tracing to follow tumor growth and metastasis to understand the contribution of different cell types in cancer progression. GEMMs are widely used for therapeutic optimization. In this review, we summarize the main molecular alterations found in pancreatic neoplasms, developed GEMMs, and the contribution of GEMMs to the current understanding of PDAC pathobiology. Furthermore, we attempted to modify the categorization of altered driver genes according to the most updated findings.

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“…KRAS mutations occur in over 90% of PDACs [11] and MYC, a basic-helix-loop-helix/leucine zipper transcription factor (TF), has an important function as an integrator of signaling pathways triggered by oncogenic KRAS [12]. MYC heterodimers (e.g., MYC/MAX) bind to cisregulatory E-box sequences of numerous genes involved in the regulation of growth, proliferation, or metabolism, thereby serving all hallmark demands of cancer cells [13,14]. MYC marks an aggressive PDAC subtype, which is supported by the fact that amplifications of MYC have been associated with a worse survival of PDAC patients [15].…”

Section: An Update Of Myc-driven Biology In Pdacmentioning

confidence: 99%

Rationale for MYC imaging and targeting in pancreatic cancer

et al. 2021

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The incidence and lethality of pancreatic ductal adenocarcinoma (PDAC) will continue to increase in the next decade. For most patients, chemotherapeutic combination therapies remain the standard of care. The development and successful implementation of precision oncology in other gastrointestinal tumor entities point to opportunities also for PDAC. Therefore, markers linked to specific therapeutic responses and important subgroups of the disease are needed. The MYC oncogene is a relevant driver in PDAC and is linked to drug resistance and sensitivity. Here, we update recent insights into MYC biology in PDAC, summarize the connections between MYC and drug responses, and point to an opportunity to image MYC non-invasively. In sum, we propose MYC-associated biology as a basis for the development of concepts for precision oncology in PDAC.

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Targeting MYC: From understanding its biology to drug discovery

Cited by 23 publications

References 140 publications

Thyroid Carcinoma with NSD3::NUTM1 Fusion: a Case with Thyrocyte Differentiation and Colloid Production

Thyroid Carcinoma with NSD3::NUTM1 Fusion: a Case with Thyrocyte Differentiation and Colloid Production

Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models

Rationale for MYC imaging and targeting in pancreatic cancer

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