Multiple proliferation-survival signalling pathways are simultaneously active in BRAF V600E mutated thyroid carcinomas

Rahman, Atiqur; Salajegheh, Ali; Smith, Robert A.; Lam, Alfred King‐Yin

doi:10.1016/j.yexmp.2015.09.006

Cited by 17 publications

(14 citation statements)

References 26 publications

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“…The coexistence of BRAFV600E mutation and EGFR overexpression indicates that multiple signaling pathways are simultaneously active in some BRAFV600E-mutated thyroid carcinomas. Furthermore, our results obtained in a clinical setting confirm the findings of a recent in vitro study in which both active MAPK and PI3K/Akt pathways were found in BRAFV600E-mutated thyroid carcinoma cells in culture [33].…”

Section: Discussionsupporting

confidence: 90%

“…Advanced BRAF mutated thyroid carcinomas are characterized by the loss of thyroid-specific characters and poor responsiveness to radioiodine therapy and thus require new therapeutic options [10]. In vitro studies have demonstrated that thyroid malignant cells bearing BRAF mutations are, unlike melanoma but similarly to colorectal cancer, less sensitive to BRAF inhibitors due to the activation of alternative signaling pathways [33,36]. Furthermore, it has been reported that combined inhibition of BRAF and EGFR signaling in malignant thyroid cells (by vemurafenib and gefitinib) was more effective than vemurafenib or gefitinib single agents, and resulted in the induction of synthetic lethality [37,38].…”

Section: Discussionmentioning

confidence: 99%

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Coexistence of BRAFV600E mutation and EGFR overexpression is highly associated with adverse clinicopathological features of papillary thyroid carcinoma

Paunović

Šelemetjev

Denčić

et al. 2020

ARCH BIOL SCI BELGRA

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Papillary thyroid carcinoma (PTC) generally has a good prognosis, but in a subset of patients it progresses to aggressive forms. Analysis of molecular alterations in relation to clinical phenotype may help in risk stratification of patients by predicting tumor aggressiveness. We analyzed the expression profiles of epidermal growth factor receptor (EGFR) using immunohistochemistry and the presence of BRAF(V600E) mutation by mutant allele-specific PCR in PTC tissue samples (n=92) in relation to clinicopathological parameters. BRAFV600E was detected in 46.7% of patients and correlated with the presence of lymph node metastasis (LNM, p=0.035) and extrathyroid invasion (EI, p<0.0001). EGFR overexpression was detected in 52.2% of the patients and also correlated with LNM (p<0.0001) and EI (p=0.027). Among patients with a single alteration, the presence of BRAFV600E impacted EI, while EGFR overexpression alone had a greater impact on LNM. The strongest association with adverse features was found in PTC patients with coexisting BRAFV600E and EGFR overexpression (28.3%), among whom LNM and EI were evident in 73% and 69%, respectively (p<0.0001, for both). Thus, the coexistence of BRAFV600E mutation and EGFR overexpression identifies high-risk PTC patients, who should be considered for combined molecular therapy offering a better long-term therapeutic outcome.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Coexistence of BRAFV600E mutation and EGFR overexpression is highly associated with adverse clinicopathological features of papillary thyroid carcinoma

Paunović

Šelemetjev

Denčić

et al. 2020

ARCH BIOL SCI BELGRA

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“…The mitogen-activated protein kinase (MAPK) and PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) pathways are major pathways for pathogenesis of follicular-derived thyroid carcinoma (Rahman et al 2015). Interactions of these two pathways were demonstrated in follicularderived thyroid carcinoma (Rahman et al 2016).…”

Section: Mapk and Pi3k/act Pathways And Tertmentioning

confidence: 99%

Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer

Lam¹,

Saremi²

2017

Endocrine-Related Cancer

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The aim of this systematic review is to study the features of cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) by analysing the 129 documented cases in the English literature. The disease occurred almost exclusively in women. The median age of presentation for CMV-PTC was 24 years. Slightly over half of the patients with CMV-PTC had familial adenomatous polyposis (FAP). CMV-PTC presented before the colonic manifestations in approximately half of the patients with FAP. Patients with FAP often have multifocal tumours in the thyroid. Microscopic examination of CMV-PTC revealed predominately cribriform and morular pattern of cancer cells with characteristic nuclear features of papillary thyroid carcinoma. Psammoma body is rare. On immunohistochemical studies, β-catenin is diffusely positive in CMV-PTC. The morular cells in CMV-PTC are strongly positive for CD10, bcl-2 and E-cadherin. Pre-operative diagnosis of CMV-PTC by fine-needle aspiration biopsy could be aided by cribriform architecture, epithelial morules and β-catenin immunostaining. Mutations of APC gene are found in the patients with CMV-PTC associated with FAP. In addition, mutations in CTNNB1, RET/PTC rearrangement and PI3K3CA mutations have been reported. BRAF mutation is negative in all CMV-PTC tested. Compared to conventional papillary thyroid carcinoma, CMV-PTC had a lower frequency of lymph node metastases at presentation (12%) and distant metastases (3%) as well as lower recurrence rates (8.5%) and patients' mortality rates (2%). To conclude, patients with CMV-PTC have distinctive clinical, pathological and molecular profiles when compared to conventional papillary thyroid carcinoma.

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“…The activating mutation BRAFV600E was originally reported in melanoma, but has subsequently been identified as a driver mutation in several other cancers, such as colon cancer and thyroid cancer [62, 63]. Selected targeting inhibitors including vemurafenib and dabrafenib have been tested in clinical trials for melanoma since 2008, and demonstrated high response rates and a significant prolongation in survival [63, 64].…”

Section: Immunomodulatory Effects Of Small-molecule Inhibitorsmentioning

confidence: 99%

“…Selected targeting inhibitors including vemurafenib and dabrafenib have been tested in clinical trials for melanoma since 2008, and demonstrated high response rates and a significant prolongation in survival [63, 64]. There is accumulating evidence indicating that the therapeutic efficacy of BRAF inhibitors depends on their ability to generate a tumor specific immune response.…”

Section: Immunomodulatory Effects Of Small-molecule Inhibitorsmentioning

confidence: 99%

The Role of Adaptive Immunity in the Efficacy of Targeted Cancer Therapies

Zhang

et al. 2016

Trends in Immunology

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Accumulating evidence indicates that the efficacy of tumor targeted therapies relies on the host immune response, including targeted small molecule and antibody approaches that were not previously thought to have an immune component. Here we review the current understanding of how targeted therapies on tumor cells could have a major impact on the immune response, and how this relates to the therapeutic efficacy of these approaches. In this context we evaluate different strategies that combine targeted therapies with immunotherapy approaches, and discuss past and ongoing clinical trials. We highlight gaps in knowledge, and argue that significant progress for combined therapies will require a better understanding of the complex interactions between immune cells, the tumor and the tumor microenvironment in different cancer settings.

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Multiple proliferation-survival signalling pathways are simultaneously active in BRAF V600E mutated thyroid carcinomas

Cited by 17 publications

References 26 publications

Coexistence of BRAFV600E mutation and EGFR overexpression is highly associated with adverse clinicopathological features of papillary thyroid carcinoma

Coexistence of BRAFV600E mutation and EGFR overexpression is highly associated with adverse clinicopathological features of papillary thyroid carcinoma

Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer

The Role of Adaptive Immunity in the Efficacy of Targeted Cancer Therapies

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