A research perspective published in Volume 13 of Oncoscience on June 3, 2026, examines how two interconnected signaling pathways drive the development and progression of papillary thyroid carcinoma. The article, authored by Gunvanti Rathod and Pragnesh Parmar from AIIMS Bibinagar, India, discusses the role of the mitogen-activated protein kinase (MAPK) pathway and the PI3K/AKT pathway in this common type of thyroid cancer.
Papillary thyroid carcinoma accounts for approximately 80–85% of thyroid cancers and is generally associated with excellent long-term survival. However, some tumors behave more aggressively by invading surrounding tissues or recurring after treatment. The authors say that understanding molecular changes distinguishing these aggressive tumors has become a major focus in research.
The review explains that MAPK signaling is a primary driver during early tumor development. Alterations involving BRAF and RAS genes, as well as RET/PTC rearrangements and NTRK fusions, activate this pathway. The most common alteration, BRAF V600E, occurs in about 40–60% of cases and is linked to more aggressive disease along with reduced responsiveness to radioactive iodine therapy. Persistent activation also suppresses genes involved in iodine uptake.
As disease progresses, the PI3K/AKT pathway becomes increasingly involved through alterations affecting PIK3CA, PTEN, and AKT genes. These changes enhance cell survival mechanisms such as angiogenesis and resistance to apoptosis. Such abnormalities are uncommon at early stages but appear more frequently in poorly differentiated or anaplastic cancers.
The authors say that rather than acting independently, MAPK and PI3K/AKT pathways interact via shared receptors such as RET or EGFR, along with feedback mechanisms mediated by RAS proteins. This crosstalk allows cancer cells to adapt when one pathway is blocked therapeutically: "Development of novel molecular diagnostics tests and targeted therapies helped to enhance personalized treatment approaches in papillary thyroid carcinoma patients. The future might hold new approaches in combinational therapy of aggressive and therapy-resistant forms of papillary thyroid carcinoma." Combination therapies targeting both networks are under investigation for overcoming resistance.
Molecular testing for specific mutations can help refine risk assessment for indeterminate nodules identified by fine-needle aspiration cytology while guiding use of targeted drugs like BRAF inhibitors or multikinase agents such as lenvatinib or cabozantinib; therapies targeting PI3K/AKT/mTOR remain investigational. The authors conclude that a better understanding of these interacting pathways may support improved risk assessment and more precise use of targeted treatments.
