MAPK Pathway Inhibitors in Thyroid Cancer: Preclinical and Clinical Data

Simple Summary The Ras-Raf-MEK-ERK signaling pathway is responsible for regulating cell proliferation, differentiation and survival. Overexpression and overactivation of members within the signaling cascade have been observed in many solid cancers and especially in thyroid cancers. These members are therefore the target of inhibitory therapies, for example tyrosine kinase inhibitors or monoclonal antibodies. These drugs are already used in clinical practice, but their efficacy is not always satisfactory, and they could be subject to escape phenomenon. This is the reason why research is focusing on developing new molecules. We aimed to provide an overview of the MAPK pathway's physiologic regulation. Furthermore, we summarized the preclinical and clinical studies including redifferentiation studies that used MAPK pathway inhibitors in thyroid cancers. 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 BRAF(V600E) 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 BRAF(V600E) 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.

Automated summary

The Ras-Raf-MEK-ERK signaling pathway plays a crucial role in regulating cell proliferation, differentiation, and survival. Its dysregulation is associated with many solid cancers, particularly thyroid cancers. While targeted therapies such as tyrosine kinase inhibitors and monoclonal antibodies are used in clinical practice, their efficacy is not always satisfactory. Therefore, there is a need for the development of new molecules. This study provides an overview of the physiological regulation of the MAPK pathway and summarizes the preclinical and clinical studies on the use of MAPK pathway inhibitors in thyroid cancers, including redifferentiation studies.