Genetic Alterations in MAPK/PI3K Pathways and Their Impact on Radioiodine Therapy in Differentiated Thyroid Cancer

Abstract

Differentiated thyroid cancer (DTC), primarily papillary (PTC) and follicular (FTC) subtypes, usually follows a favorable course after total or near-total thyroidectomy combined with radioactive iodine (RAI, I-131) ablation. Nevertheless, 10–15% of patients experience recurrence, distant metastases, or progression to radioiodine-refractory thyroid cancer (RAIR-TC), which represents the major cause of disease-specific mortality in DTC [1]. Such variability in treatment response strongly suggests that underlying molecular factors play a decisive role. Among these, genetic alterations in oncogenic pathways, particularly MAPK (Ras → Raf → MEK → ERK) and PI3K (PI3K → AKT → mTOR), are critical determinants of cell differentiation, invasive behavior, and iodide uptake [1]. Understanding these alterations provides a rational framework for predicting RAI failure and guiding individualized therapeutic strategies.