What are the molecular mechanisms underlying the disruption of Sodium-Iodide Symporter (NIS) expression in advanced Differentiated Thyroid Cancer (DTC), including the role of Phosphatidylinositol 3-kinase (PI3K)/Protein Kinase B (AKT) signaling, Mitogen-Activated Protein Kinase (MAPK) overactivation, and post-translational modifications?

From the Guidelines

The statements about PI3K/AKT signaling in differentiated thyroid cancer (DTC) and the mechanisms of radioiodine resistance are supported by multiple research publications in the field of thyroid cancer biology, as documented in studies such as those by Xing (2010) and Liu et al. (2013) 1. The activation of PI3K/AKT pathway in advanced DTC has been documented in several studies, including those by Xing (2010) and Liu et al. (2013) 1.

• The role of PIK3CA, AKT1 mutations, and PTEN loss in reducing sodium iodide symporter (NIS) expression was demonstrated by Kogai et al. (2008) and Hou et al. (2010) 1.
• Regarding MAPK pathway effects on NIS expression, the transcriptional repression mechanisms were elucidated by Riesco-Eizaguirre et al. (2009), while the involvement of TGF-β–Smad and NF-κB signaling was described by Knauf and Fagin (2009) 1.
• The post-translational modifications affecting NIS membrane localization were reported by Darrouzet et al. (2014) and Wapnir et al. (2003) 1. These molecular mechanisms collectively explain why advanced thyroid cancers often become resistant to radioactive iodine therapy, which is critical information for developing targeted therapies to restore iodine uptake. The most recent and highest quality study on this topic is the 2022 ESMO clinical practice guideline update on the use of systemic therapy in advanced thyroid cancer, which provides a comprehensive overview of the current state of knowledge in this field 1.
• This guideline update discusses the role of PI3K/AKT signaling and other molecular mechanisms in the development of resistance to radioactive iodine therapy in advanced DTC.
• It also provides recommendations for the management of patients with advanced DTC, including the use of targeted therapies and other systemic treatments. Overall, the evidence suggests that the activation of PI3K/AKT signaling and other molecular mechanisms play a critical role in the development of resistance to radioactive iodine therapy in advanced DTC, and that targeted therapies may be effective in restoring iodine uptake and improving patient outcomes 1.

From the Research

Activation of PI3K/AKT Signaling

• The activation of PI3K/AKT signaling is a common occurrence in advanced DTC, with mutations in PIK3CA, AKT1, and loss of PTEN facilitating proliferation and reducing NIS expression 2, 3, 4.
• These pathways also support angiogenesis, metabolic reprogramming, and apoptotic resistance, contributing to cancer progression and treatment resistance 3, 4.

MAPK Overactivation

• MAPK overactivation disrupts NIS expression via transcriptional repression, reduced histone acetylation, and inhibition of the NIS upstream enhancer (NUE) through TGF-β–Smad and NF-κB signaling 5, 6.
• The interplay between the PI3K-AKT-mTOR pathway and the MAPK signaling cascade can promote cancer growth and drug-resistance, highlighting the need for combination therapies targeting multiple pathways 5, 6.

Post-Translational Modifications

• Aberrant glycosylation and defective trafficking can impair NIS membrane localization, reinforcing resistance to RAI therapy 5.
• Targeting the PI3K and MAPK signaling pathways may enhance chemoradiotherapy in locally advanced rectal cancer, as demonstrated by the synergistic effects of PI3K and MEK inhibitors in vitro and in vivo 5.