Activating BRAF and PIK3CA Mutations Cooperate to Promote Anaplastic Thyroid Carcinogenesis

Charles, Roch‐Philippe; Silva, Jillian; Iezza, Gioia; Phillips, Wayne A.; McMahon, Martin

doi:10.1158/1541-7786.mcr-14-0158-t

Cited by 93 publications

(80 citation statements)

References 26 publications

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“…Others recapitulate phenotypes observed in genetically engineered mouse models of advanced thyroid cancers, such as PTEN and TP53 (53), BRAF and TP53 (54), RAS and TP53 (55), RAS and NF2 (52), and BRAF and PIK3CA (56).…”

Section: Discussionmentioning

confidence: 79%

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Landa¹,

Ibrahimpašić²,

Boucai³

et al. 2016

Journal of Clinical Investigation

946

1,212

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IntroductionA comprehensive investigation of the genomic landscape of papillary thyroid carcinomas (PTC), the most common thyroid malignancy, was recently reported by The Cancer Genome Atlas Network (TCGA Network) (1). These well-differentiated tumors were found to have a low frequency of somatic alterations (2), with the majority harboring mutually exclusive activating mutations in BRAF (60%) and RAS-family genes (13%), as well as fusion oncoproteins, primarily involving receptor tyrosine kinases (RTKs) such as RET, NTRK1 or -3, and ALK. Distinct signaling and transcriptomic consequences were observed between BRAF V600E -like tumors, which showed higher MAPK transcriptional output and lower expression of genes involved in iodine metabolism, and RAS-like tumors, which had lower MAPK signaling and comparatively preserved expression of iodine-related genes.The TCGA study excluded poorly differentiated thryoid cancers (PDTCs) and anaplastic thyroid cancers (ATCs) from their analysis in order to focus on a homogeneous histological cohort that would provide sufficient power to identify low-frequency genomic events. Although PDTCs and ATCs account for approximately 5%-10% of thyroid cancers, they represent a major clinical challenge. Patients with PDTC and ATC have a mean survival after diagnosis of 3.2 and 0.5 years, respectively, and account for approximately a third of deaths caused by this disease (3). Virtually all cases are refractory to radioiodine therapy, and traditional chemotherapy and radiotherapy are of marginal benefit (4, 5).Molecularly targeted approaches are being tested in preclinical BACKGROUND. Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization. METHODS.We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC). RESULTS.Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs w...

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Section: Discussionmentioning

confidence: 79%

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Landa¹,

Ibrahimpašić²,

Boucai³

et al. 2016

Journal of Clinical Investigation

946

1,212

View full text Add to dashboard Cite

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“…The past few years have thus seen the generation and exploitation of highly relevant mouse models for follicular (Antico-Arciuch, et al 2010; Pringle, et al 2014; Suzuki, et al 2002), papillary (Chakravarty, et al 2011; Jhiang, et al 1996; Knauf, et al 2005), and anaplastic thyroid cancer (Antico Arciuch, et al 2011; Charles, et al 2014; McFadden, et al 2014). Areas of poor differentiation were instead observed in advanced papillary tumors developed by BRAF V600E mice (Knauf, et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression

Champa¹,

Russo²,

Liao³

et al. 2014

Endocrine Related Cancer

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Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 in thyroid follicular cells, we have developed a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. In several cases, tumors further progress to anaplastic carcinomas. The poorly differentiated tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Using primary carcinomas as well as carcinoma-derived cell lines, we also demonstrate that these tumors are intrinsically resistant to apoptosis due to high levels of expression of the Bcl2 family members Bcl2a1 and Mcl1, and can be effectively targeted by Obatoclax, a small molecule pan-inhibitor of the Bcl2 family. Furthermore, we show that Bcl2 family inhibition synergizes with MEK inhibition as well as with doxorubicin in inducing cell death. Thus, our studies in a novel, relevant mouse model, uncover a promising druggable feature of aggressive thyroid cancers.

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“…[66][67][68][69] In the recent past, a number of transgenic mice have been developed that mimic ATC in vivo [70][71][72][73] and serve as much more clinically relevant models for preclinical testing. These models have primarily been used to elucidate the hypothesis that ATCs arise as a progression from PTC or FTC due to hits to multiple signaling pathways and therefore provide the closest simulation environment reflective of direct in human testing.…”

Section: Preclinical and Clinical Studies Evaluating Potential Therapiesmentioning

confidence: 99%

Anaplastic thyroid cancer – an overview of genetic variations and treatment modalities

Reddi¹,

Kumar²,

Kulstad³

2015

AGG

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Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive malignancy that accounts for about 1%-2% of all thyroid cancer diagnoses but is responsible for up to 30%-40% of thyroid cancer deaths. ATCs are poorly differentiated tumors that develop on the background of preexisting, often undiagnosed, papillary thyroid carcinoma or follicular thyroid carcinoma, through progressive accumulation of changes in several oncogenic and tumor suppressor pathways, including p53, RAS, RAF, Wnt-β-catenin and the PTEN-AKT pathways. Consequently, the 1-year survival rate after diagnosis ranges from 5% to 15%. Current therapeutic approaches are aimed at common late oncogenic changes and involve inhibition of MAPK and PI3K cell proliferation pathways or restoration of p53 and PTEN tumor suppressor pathways. Since singlemodality therapy has limited effect on anaplastic thyroid cancer, aggressive multimodal treatments are now the treatment of choice, in spite of which, the mean survival time from diagnosis to death continues to remain at about 6 months. The current review attempts to summarize the genetics involved in the development and progression of ATC and provides some insight into the therapeutic options being evaluated for this aggressive cancer.

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Activating BRAF and PIK3CA Mutations Cooperate to Promote Anaplastic Thyroid Carcinogenesis

Cited by 93 publications

References 26 publications

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression

Anaplastic thyroid cancer – an overview of genetic variations and treatment modalities

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Activating BRAF and PIK3CA Mutations Cooperate to Promote Anaplastic Thyroid Carcinogenesis

Cited by 93 publications

References 26 publications

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression

Anaplastic thyroid cancer &ndash; an overview of genetic variations and treatment modalities

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Anaplastic thyroid cancer – an overview of genetic variations and treatment modalities