MAPK Pathway Inhibitors in Thyroid Cancer: Preclinical and Clinical Data

• Published in: Cancers Vol. 15; no. 3; p. 710
• Main Authors: Schubert, Louis, Mariko, Mohamed Lamine, Clerc, Jérôme, Huillard, Olivier, Groussin, Lionel
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24-01-2023; MDPI
• Subjects: Apoptosis; Cancer therapies; Cell differentiation; Cell proliferation; Cell survival; Development and progression; Drug therapy; Extracellular signal-regulated kinase; Growth factors; Health aspects; Iodine; Kinases; MAP kinase; Medical prognosis; MEK inhibitors; Melanoma; Metastases; Metastasis; Mitogen-activated protein kinases; Monoclonal antibodies; Mutation; Mutation hot spots; Phosphorylation; Physiological aspects; Protein-tyrosine kinase; Proteins; Raf protein; Review; Signal transduction; Thyroid cancer; Thyroidectomy; Tumors; France; MAPK pathway; radioactive iodine; targeted therapy; BRAF; thyroid cancer; redifferentiation
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15030710

Thyroid cancer is the most common endocrine cancer, with a good prognosis in most cases. However, some cancers of follicular origin are metastatic or recurrent and eventually become radioiodine refractory thyroid cancers (RAIR-TC). These more aggressive cancers are a clinical concern for which the therapeutic arsenal remains limited. Molecular biology of these tumors has highlighted a hyper-activation of the Mitogen-Activated Protein Kinases (MAPK) pathway (RAS-RAF-MEK-ERK), mostly secondary to the
hotspot mutation occurring in about 60% of papillary cancers and 45% of anaplastic cancers. Therapies targeting the different protagonists of this signaling pathway have been tested in preclinical and clinical models: first and second generation RAF inhibitors and MEK inhibitors. In clinical practice, dual therapies with a BRAF inhibitor and a MEK inhibitor are being recommended in anaplastic cancers with the
mutation. Concerning RAIR-TC, these inhibitors can be used as anti-proliferative drugs, but their efficacy is inconsistent due to primary or secondary resistance. A specific therapeutic approach in thyroid cancers consists of performing a short-term treatment with these MAPK pathway inhibitors to evaluate their capacity to redifferentiate a refractory tumor, with the aim of retreating the patients by radioactive iodine therapy in case of re-expression of the sodium-iodide symporter (NIS). In this work, we report data from recent preclinical and clinical studies on the efficacy of MAPK pathway inhibitors and their resistance mechanisms. We will also report the different preclinical and clinical studies that have investigated the redifferentiation with these therapies.