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Open AccessReview

BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives

1
Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy
2
Nuclear Medicine Unit, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy
3
Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71121 Foggia, Italy
*
Authors to whom correspondence should be addressed.
These authors have contributed equally to this work.
Cancers 2019, 11(9), 1388; https://doi.org/10.3390/cancers11091388
Received: 30 August 2019 / Accepted: 10 September 2019 / Published: 18 September 2019
(This article belongs to the Special Issue Thyroid Cancer)
The Kirsten rat sarcoma viral oncogene homolog (RAS)/v-raf-1 murine leukemia viral oncogene homolog 1 (RAF)/mitogen-activated protein kinase 1 (MAPK) signaling cascade is the most important oncogenic pathway in human cancers. Tumors leading mutations in the gene encoding for v-raf murine sarcoma viral oncogene homolog B (BRAF) serine-threonine kinase are reliant on the MAPK signaling pathway for their growth and survival. Indeed, the constitutive activation of MAPK pathway results in continuous stimulation of cell proliferation, enhancement of the apoptotic threshold and induction of a migratory and metastatic phenotype. In a clinical perspective, this scenario opens to the possibility of targeting BRAF pathway for therapy. Thyroid carcinomas (TCs) bearing BRAF mutations represent approximately 29–83% of human thyroid malignancies and, differently from melanomas, are less sensitive to BRAF inhibitors and develop primary or acquired resistance due to mutational events or activation of alternative signaling pathways able to reactivate ERK signaling. In this review, we provide an overview on the current knowledge concerning the mechanisms leading to resistance to BRAF inhibitors in human thyroid carcinomas and discuss the potential therapeutic strategies, including combinations of BRAF inhibitors with other targeted agents, which might be employed to overcome drug resistance and potentiate the activity of single agent BRAF inhibitors. View Full-Text
Keywords: BRAF mutation; thyroid cancer; BRAF inhibitors; mechanism of resistance BRAF mutation; thyroid cancer; BRAF inhibitors; mechanism of resistance
MDPI and ACS Style

Crispo, F.; Notarangelo, T.; Pietrafesa, M.; Lettini, G.; Storto, G.; Sgambato, A.; Maddalena, F.; Landriscina, M. BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives. Cancers 2019, 11, 1388.

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