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Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer

ABSTRACT: Our findings establish that BRAF- and RAS-mutant thyroid cells respond differentially to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 demonstrated significant anti-tumor effects in vivo with an apparent lack of toxicity, making it an interesting candidate for the development of combinatorial treatments. Thus, our data underscore the differences elicited by the specific driver mutation for thyroid cancer onset and progression, which should be considered for experimental and clinical approaches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190711 | GEO | 2021/12/15

REPOSITORIES: GEO

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Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer.

Project description:BackgroundRAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic benefit in several human carcinomas. Here we analyzed the effects of DEL-22379, a relatively specific ERK dimerization inhibitor, on the activation of the RAS-to-ERK signaling cascade and on tumor-related processes in vitro and in vivo.MethodsWe used a panel of four human anaplastic thyroid carcinoma (ATC) cell lines harboring BRAF or RAS mutations to analyze ERK dynamics and tumor-specific characteristics. We also assessed the impact of DEL-22379 on the transcriptional landscape of ATC cell lines using RNA-sequencing and evaluated its therapeutic efficacy in an orthotopic mouse model of ATC.ResultsDEL-22379 impaired upstream ERK activation in BRAF- but not RAS-mutant cells. Cell viability and metastasis-related processes were attenuated by DEL-22379 treatment, but mostly in BRAF-mutant cells, whereas in vivo tumor growth and dissemination were strongly reduced for BRAF-mutant cells and mildly reduced for RAS-mutant cells. Transcriptomics analyses indicated that DEL-22379 modulated the transcriptional landscape of BRAF- and RAS-mutant cells in opposite directions.ConclusionsOur findings establish that BRAF- and RAS-mutant thyroid cells respond differentially to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 demonstrated significant anti-tumor effects against BRAF-mutant cells in vivo with an apparent lack of toxicity, making it an interesting candidate for the development of combinatorial treatments. Our data underscore the differences elicited by the specific driver mutation for thyroid cancer onset and progression, which should be considered for experimental and clinical approaches.

| S-EPMC9440884 | biostudies-literature

Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer

Project description:Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer

| PRJNA788144 | ENA

Effects of BRAF and ERK inhibition on papillary and anaplastic thyroid cancer

Project description:To investigate the effects of combined BRAF inhibition (dabrafenib) and ERK inhibition (ulixertinib) on papillary and anaplastic thyroid cancer transcriptional reprogramming

2023-06-15 | GSE221329 | GEO

Effects of BRAF and ERK inhibition on papillary and anaplastic thyroid cancer

Project description:Effects of BRAF and ERK inhibition on papillary and anaplastic thyroid cancer

| PRJNA913907 | ENA

p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer.

Project description:Anaplastic thyroid carcinoma (ATC) has among the worst prognosis of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. BRAF and TP53 mutations co-occur in a high proportion of ATC, particularly those associated with a precursor papillary thyroid carcinoma (PTC). In order to develop an adult-onset model of BRAF-mutant anaplastic thyroid carcinoma, we generated a novel thyroid-specific CreER transgenic mouse. We utilize a Cre-regulated BrafV600E mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from papillary to anaplastic thyroid carcinoma. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis and rapid lethality. We employed small animal ultrasound imaging to monitor autochthonous tumors, and show that treatment with the selective BRAF inhibitor PLX4720 improved survival, but did not lead to tumor regression or suppress signaling through the MAPK pathway. Combination of PLX4720 and the MEK inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines, and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma. Total RNA from five murine papillary thyroid carcinoma (PTC) tumors and five murine anaplastic thyroid carcinoma (ATC) tumors was analyzed.

2014-04-02 | E-GEOD-55933 | biostudies-arrayexpress

p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer.

2014-04-02 | GSE55933 | GEO

Co-evolution of Met amplification and Hgf overexpression mediate resistance to BRAF inactivation in mouse anaplastic thyroid cancers.

Project description:Affymetric arrays were performed on thyroid samples collected from GEMMs: normal thyroid, TPO-Cre/LSL-Braf (PTC), TPO-Cre/tetO-BRAF/LSL-rtTAiresGFP/p53-flox (ATC) and TPO-Cre/tetO-BRAF/LSL-rtTAiresGFP/p53-flox (recurrent tumors) As above

2018-08-02 | GSE118022 | GEO

Genomic and Transcriptomic Hallmarks of Poorly-Differentiated and Anaplastic Thyroid Cancers

Project description:BACKGROUND. Poorly-differentiated (PDTC) and anaplastic (ATC) thyroid cancers are rare and frequently lethal tumors, which so far have not been subjected to comprehensive genetic characterization. METHODS. We performed next generation sequencing of 341 cancer genes in 117 PDTCs and ATCs, and a transcriptomic analysis of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas (TCGA) study of papillary thyroid cancers (PTC). RESULTS. ATCs have a greater mutation burden than PDTCs, and higher mutation frequency of TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits and histone methyltransferases. BRAF and RAS are the predominant drivers, and dictate remarkably distinct tropism for nodal vs. distant metastases in PDTC. RAS and BRAF sharply distinguish between PDTCs defined by the Turin (PDTC-Turin) vs. MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, are markedly enriched in PDTCs and ATCs, and have a striking pattern of co-occurrence with RAS. TERT promoter mutations are rare and subclonal in PTCs, whereas they are clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) shows a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs are BRAF-like irrespective of driver mutation. CONCLUSIONS. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared to PDTC underscore their greater virulence and higher mortality. 37 tumor specimens, including 17 poorly-differentiated and 20 anaplastic thyroid cancers were expression-profiled with Affymetrix U133 plus 2.0 array

2016-02-15 | E-GEOD-76039 | biostudies-arrayexpress

Melatonin synergizes BRAF-targeting agent dabrafenib for the treatment of anaplastic thyroid cancer by inhibiting AKT/hTERT signalling.

Project description:As a selective inhibitor of BRAF kinase, dabrafenib has shown potent anti-tumour activities in patients with BRAFV600E mutant anaplastic thyroid cancer. However, the resistance of thyroid cancer cells to dabrafenib limited its therapeutic effect. The effects of melatonin and dabrafenib as monotherapy or in combination on the proliferation, cell cycle arrest, apoptosis, migration and invasion of anaplastic thyroid cancer cells were examined. The molecular mechanism involved in drug combinations was also revealed. Melatonin enhanced dabrafenib-mediated inhibition of cell proliferation, migration and invasion, and promoted dabrafenib-induced apoptosis and cell cycle arrest in anaplastic thyroid cancer cells. Molecular mechanistic studies further uncovered that melatonin synergized with dabrafenib to inhibit AKT and EMT signalling pathways. Furthermore, melatonin and dabrafenib synergistically inhibited the expression of hTERT, and the inhibition of cell viability and the induction of cell cycle arrest mediated by the combination of these two drugs were reversed by hTERT overexpression. Taken together, our results demonstrated that melatonin synergized the anti-tumour effect of dabrafenib in human anaplastic thyroid cancer cells by inhibiting multiple signalling pathways, and provided new insights in exploring the potential therapeutic targets for the treatment of anaplastic thyroid cancer.

| S-EPMC7579709 | biostudies-literature

T-cell-derived Hodgkin lymphoma has motility characteristics intermediate between Hodgkin and anaplastic large cell lymphoma

Project description:Global proteomics profiling of anaplastic large cell lymphoma cell lines DEL, SU-DHL-1 (ALK+), Mac-1, Mac-2A (ALK-) as well as Hodgkin lymphoma cell lines L-428, L-540, L-1236 and HDLM-2.

2022-08-12 | PXD031907 | Pride

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