Vemurafenib Redifferentiation of <i>BRAF</i> Mutant, RAI-Refractory Thyroid Cancers

Dunn, Lara; Sherman, Eric J.; Baxi, Shrujal S.; Tchekmedyian, Vatche; Grewal, Ravinder K.; Larson, Steven M.; Pentlow, Keith S.; Haque, Sofia; Tuttle, R. Michael; Sabra, Mona M.; Fish, Stephanie; Boucai, Laura; Walters, Jamie; Ghossein, Ronald; Seshan, Venkatraman; Ni, Ai; Li, Duan; Knauf, Jeffrey A.; Pfister, David G.; Fagin, James A.; Ho, Alan L.

doi:10.1210/jc.2018-01478

Cited by 190 publications

(143 citation statements)

References 29 publications

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“…Based on these studies, MEK inhibitors and BRAF inhibitors have been developed for BRAF-and RAS-mutated TC patients. Pilot clinical studies in RAI-refractory patients showed an increase in the RAI avidity and tumour response following RAI treatment, when it was preceded by treatment with a MEK inhibitor (selumetinib) or a BRAF inhibitor (dabrafenib or vemurafenib) in patients with a RAS or BRAF V600E mutation (Ho et al 2013, Rothenberg et al 2015, Dunn et al 2018). Unfortunately, not all patients respond to these treatments, and further inhibition of the MAPK pathway with combination treatment is being investigated.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress in thyroid carcinomas: biological and clinical significance

Hassani

Buffet

Leboulleux

et al. 2019

Endocrine-Related Cancer

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At physiological concentrations, reactive oxygen species (ROS), including superoxide anions and H2O2, are considered as second messengers that play key roles in cellular functions, such as proliferation, gene expression, host defence and hormone synthesis. However, when they are at supraphysiological levels, ROS are considered potent DNA-damaging agents. Their increase induces oxidative stress, which can initiate and maintain genomic instability. The thyroid gland represents a good model for studying the impact of oxidative stress on genomic instability. Indeed, one particularity of this organ is that follicular thyroid cells synthesise thyroid hormones through a complex mechanism that requires H2O2. Because of their detection in thyroid adenomas and in early cell transformation, both oxidative stress and DNA damage are believed to be neoplasia-preceding events in thyroid cells. Oxidative DNA damage is, in addition, detected in the advanced stages of thyroid cancer, suggesting that oxidative lesions of DNA also contribute to the maintenance of genomic instability during the subsequent phases of tumourigenesis. Finally, ionizing radiation and the mutation of oncogenes, such as RAS and BRAF, play a key role in thyroid carcinogenesis through separate and unique mechanisms: they upregulate the expression of two distinct ‘professional’ ROS-generating systems, the NADPH oxidases DUOX1 and NOX4, which cause DNA damage that may promote chromosomal instability, tumourigenesis and dedifferentiation.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress in thyroid carcinomas: biological and clinical significance

Hassani

Buffet

Leboulleux

et al. 2019

Endocrine-Related Cancer

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“…More recently, Huillard and colleagues investigated the ability of vemurafenib in inducing tumor redifferentiation and in restoring RAI uptake in an 83-year-old man with BRAF V600E -mutant RR-DTC and found that vemurafenib and dabrafenib could significantly enhance RAI uptake and reduce 18 F-FDG uptake (Huillard et al 2017). The redifferentiation effect of vemurafenib was further validated by a most recent study (Dunn et al 2018), in which four of the ten evaluable RR-DTC patients responded to vemurafenib treatment likely by upregulating thyroid-specific gene expression. In a preclinical study, Chakravarty et al reported the efficacy of MAPK pathway inhibitors in restoring RAI uptake in mice (Chakravarty et al 2011).…”

Section: Autophagy In Redifferentiation Of Radioiodine-refractory Thymentioning

confidence: 92%

“…has not been proven yet. Meanwhile, redifferentiation of RR-DTC emerges as a very promising approach to restore NIS expression and to enable 131 I therapy (Ho et al 2013, Rothenberg et al 2015, Dunn et al 2018. Nonetheless, novel strategies that can enhance the efficacy of TKIs and/or overcome resistance of TKIs are in urgent need to refine the clinical management of RR-DTCs and ATCs.…”

Section: Figurementioning

confidence: 99%

“…Apart from these clinically available agents, novel chemical compounds (Galluzzi et al 2017b, Chiang et al 2018, or autophagy-inducing peptides (Peraro et al 2017), could also be used to pharmacologically stimulate autophagy. Since BRAF and MEK inhibitors have been validated as effective in restoring radioiodine incorporation in clinical trials (Ho et al 2013, Rothenberg et al 2015, Huillard et al 2017, Dunn et al 2018, future studies may also explore if there is a synergistic effect in redifferentiating RR-DTC when a combination of molecularly targeted agent with autophagy activator is applied. Previous seminal studies have demonstrated that 124 Iodine-NaI PET could detect more lesions than 131 I single photon emission computed tomography (SPECT), and the former imaging modality also allowed for quantitative dosimetry (Larson et al 2017).…”

Section: Conclusion and Future Research Perspectivesmentioning

confidence: 99%

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Targeting autophagy in thyroid cancers

Wei

Hardin

Luo

2019

Endocrine-Related Cancer

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Thyroid cancer is one of the most common endocrine malignancies. Although the prognosis for the majority of thyroid cancers is relatively good, patients with metastatic, radioiodine-refractory or anaplastic thyroid cancers have an unfavorable outcome. With the gradual understanding of the oncogenic events in thyroid cancers, molecularly targeted therapy using tyrosine kinase inhibitors (TKIs) is greatly changing the therapeutic landscape of radioiodine-refractory differentiated thyroid cancers (RR-DTCs), but intrinsic and acquired drug resistance, as well as adverse effects, may limit their clinical efficacy and use. In this setting, development of synergistic treatment options is of clinical significance, which may enhance the therapeutic effect of current TKIs and further overcome the resultant drug resistance. Autophagy is a critical cellular process involved not only in protecting cells and organisms from stressors but also in the maintenance and development of various kinds of cancers. Substantial studies have explored the complex role of autophagy in thyroid cancers. Specifically, autophagy plays important roles in mediating the drug resistance of small-molecular therapeutics, in regulating the dedifferentiation process of thyroid cancers and also in affecting the treatment outcome of radioiodine therapy. Exploring how autophagy intertwines in the development and dedifferentiation process of thyroid cancers is essential, which will enable a more profound understanding of the physiopathology of thyroid cancers. More importantly, these advances may fuel future development of autophagy-targeted therapeutic strategies for patients with thyroid cancers. Herein, we summarize the most recent evidence uncovering the role of autophagy in thyroid cancers and highlight future research perspectives in this regard. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10 2021-2035. (https://doi.

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“…4 Increasing evidences, including our previous study, have demonstrated that MAPK inhibitors (MAPKi) can induce differentiation in thyroid cancer 5,6 ; however, their clinical effectiveness in restoring 131 I uptake remains insufficient. [7][8][9][10] Thought-provokingly, reinduction of 131 I uptake in DTC patients treated with sorafenib failed even in vitro study had showed promising data. 7 Besides, the BRAF V600E inhibitor dabrafenib restored new radioiodine uptake in 60% of 10 patients, but the objective response rate was only 20%.…”

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confidence: 99%

Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAF^V600E by synergistically decreasing global trimethylation of H3K27

Cheng

et al. 2020

J Cellular Molecular Medi

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Clinical efficacy of differentiation therapy with mitogen‐activated protein kinase inhibitors (MAPKi) for lethal radioiodine‐refractory papillary thyroid cancer (RR‐PTC) urgently needs to be improved and the aberrant trimethylation of histone H3 lysine 27 (H3K27) plays a vital role in BRAFV600E‐MAPK‐induced cancer dedifferentiation and drug resistance. Therefore, dual inhibition of MAPK and histone methyltransferase (EZH2) may produce more favourable treatment effects. In this study, BRAFV600E‐mutant (BCPAP and K1) and BRAF‐wild‐type (TPC‐1) PTC cells were treated with MAPKi (dabrafenib or selumetinib) or EZH2 inhibitor (tazemetostat), or in combination, and the expression of iodine‐metabolizing genes, radioiodine uptake, and toxicity were tested. We found that tazemetostat alone slightly increased iodine‐metabolizing gene expression and promoted radioiodine uptake and toxicity, irrespective of the BRAF status. However, MAPKi induced these effects preferentially in BRAFV600E mutant cells, which was robustly strengthened by tazemetostat incorporation. Mechanically, MAPKi‐induced decrease of trimethylation of H3K27 was evidently intensified by tazemetostat in BRAFV600E‐mutant cells. In conclusion, tazemetostat combined with MAPKi enhances differentiation of PTC cells harbouring BRAFV600E through synergistically decreasing global trimethylation of H3K27, representing a novel differentiation strategy.

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Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers

Cited by 190 publications

References 29 publications

Oxidative stress in thyroid carcinomas: biological and clinical significance

Oxidative stress in thyroid carcinomas: biological and clinical significance

Targeting autophagy in thyroid cancers

Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAF^V600E by synergistically decreasing global trimethylation of H3K27

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Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers

Cited by 190 publications

References 29 publications

Oxidative stress in thyroid carcinomas: biological and clinical significance

Oxidative stress in thyroid carcinomas: biological and clinical significance

Targeting autophagy in thyroid cancers

Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAFV600E by synergistically decreasing global trimethylation of H3K27

Contact Info

Product

Resources

About

Combined tazemetostat and MAPKi enhances differentiation of papillary thyroid cancer cells harbouring BRAF^V600E by synergistically decreasing global trimethylation of H3K27