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BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives.
Cancers (Basel) 2019; 11(9)C

Abstract

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.

Authors+Show Affiliations

Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy. fabiana.crispo@crob.it.Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy. tiziana.notarangelo@crob.it.Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy. michele.pietrafesa@crob.it.Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy. giacomo.lettini@crob.it.Nuclear Medicine Unit, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy. giosto24@hotmail.com.Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy. alessandro.sgambato@crob.it.Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy. francesca.maddalena@crob.it.Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy. matteo.landriscina@unifg.it. Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71121 Foggia, Italy. matteo.landriscina@unifg.it.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

31540406

Citation

Crispo, Fabiana, et al. "BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives." Cancers, vol. 11, no. 9, 2019.
Crispo F, Notarangelo T, Pietrafesa M, et al. BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives. Cancers (Basel). 2019;11(9).
Crispo, F., Notarangelo, T., Pietrafesa, M., Lettini, G., Storto, G., Sgambato, A., ... Landriscina, M. (2019). BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives. Cancers, 11(9), doi:10.3390/cancers11091388.
Crispo F, et al. BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives. Cancers (Basel). 2019 Sep 18;11(9) PubMed PMID: 31540406.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives. AU - Crispo,Fabiana, AU - Notarangelo,Tiziana, AU - Pietrafesa,Michele, AU - Lettini,Giacomo, AU - Storto,Giovanni, AU - Sgambato,Alessandro, AU - Maddalena,Francesca, AU - Landriscina,Matteo, Y1 - 2019/09/18/ PY - 2019/08/30/received PY - 2019/09/10/accepted PY - 2019/9/22/entrez KW - BRAF inhibitors KW - BRAF mutation KW - mechanism of resistance KW - thyroid cancer JF - Cancers JO - Cancers (Basel) VL - 11 IS - 9 N2 - 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. SN - 2072-6694 UR - https://www.unboundmedicine.com/medline/citation/31540406/BRAF_Inhibitors_in_Thyroid_Cancer:_Clinical_Impact,_Mechanisms_of_Resistance_and_Future_Perspectives DB - PRIME DP - Unbound Medicine ER -