“On the whole, the significant amount of inter-pathway molecular crosstalk between the MAPK and PI3K/AKT signalling pathways constitutes a crucial element responsible for tumour progression, dedifferentiation, and therapy resistance observed in papillary thyroid carcinoma.”

A new research perspective was published in Volume 13 of Oncoscience, titled “The dual axis of tumorigenesis: MAPK and PI3K/AKT pathways in papillary thyroid carcinoma.”

The research perspective was authored by first and corresponding author Gunvanti Rathod and Pragnesh Parmar, both from AIIMS Bibinagar, India.

The authors examine how two interconnected signalling pathways drive the development and progression of papillary thyroid carcinoma (PTC), the most common type of thyroid cancer, while highlighting how molecular diagnostics and targeted therapies are shaping more personalised treatment strategies.

Papillary thyroid carcinoma accounts for approximately 80–85% of thyroid cancers and is generally associated with excellent long-term survival.

However, some tumours behave much more aggressively, invading surrounding tissues, recurring after treatment, losing sensitivity to radioactive iodine therapy, and becoming increasingly difficult to treat.

Understanding the molecular changes that distinguish these tumours has become a major focus of thyroid cancer research.

Central to this process are two signalling networks: the mitogen-activated protein kinase (MAPK) pathway and the PI3K/AKT pathway.

Under normal conditions, these pathways regulate cell growth, differentiation, metabolism, survival, and programmed cell death.

In papillary thyroid carcinoma, however, genetic alterations can keep these signalling cascades persistently active, allowing cancer cells to continue proliferating, evade apoptosis, and drive disease progression. The review explains that MAPK signalling is a major driver of early tumour development.

Alterations involving BRAF and RAS, together with RET/PTC rearrangements and NTRK fusions, activate this pathway and promote continuous signalling through RAF, MEK, and ERK.

The most common alteration, BRAF V600E, occurs in approximately 40–60% of papillary thyroid carcinomas and is associated with more aggressive disease and reduced responsiveness to radioactive iodine therapy.

Persistent BRAF signalling also suppresses thyroid-specific genes involved in iodine uptake, contributing to tumour dedifferentiation and reduced responsiveness to radioactive iodine therapy.

While MAPK activation is particularly important during tumour initiation, the PI3K/AKT pathway becomes increasingly involved as the disease progresses.

Alterations affecting PIK3CA, PTEN, and AKT enhance cell survival, angiogenesis, metabolic adaptation, invasion, and resistance to apoptosis.

These abnormalities are uncommon in conventional early-stage papillary thyroid carcinoma but occur more frequently in poorly differentiated and anaplastic thyroid cancers, where they contribute to tumour progression and therapeutic resistance.

Rather than acting independently, the MAPK and PI3K/AKT pathways interact through shared receptors, signalling molecules, and feedback mechanisms.

Receptor tyrosine kinases such as RET, EGFR, VEGFR, FGFR, PDGFR, and MET can activate both pathways, while RAS proteins provide another important point of convergence.

This extensive molecular crosstalk allows cancer cells to adapt when one pathway is therapeutically blocked, helping explain why tumours often become resistant to targeted therapies.

“Development of novel molecular diagnostics tests and targeted therapies helped to enhance personalised 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.”

Molecular testing is transforming the evaluation of thyroid nodules and cancers. Although fine-needle aspiration cytology remains the standard initial diagnostic approach, approximately 15–30% of thyroid nodules yield indeterminate results.

Testing for BRAF V600E, RAS mutations, RET/PTC rearrangements, NTRK fusions, and other molecular alterations can provide additional information about malignancy risk, tumour behaviour, prognosis, and potential treatment options.

These molecular alterations also identify actionable therapeutic targets. BRAF and MEK inhibitors suppress MAPK signalling, while selective RET and TRK inhibitors target tumours carrying the corresponding gene fusions.

Multikinase inhibitors such as lenvatinib and cabozantinib are used to treat advanced radioactive iodine-refractory differentiated thyroid cancer, whereas therapies targeting PI3K, AKT, and mTOR remain under clinical investigation.

Because blocking one pathway can activate the other through compensatory signalling, combination therapies targeting both molecular networks are attracting increasing interest.

By simultaneously suppressing MAPK and PI3K/AKT signalling, these approaches aim to overcome treatment resistance and improve outcomes for patients with aggressive disease.

The authors note, however, that many combination strategies remain investigational and require further clinical validation.

Overall, the research perspective highlights papillary thyroid carcinoma as a disease driven by interacting molecular pathways rather than a single genetic alteration.

A better understanding of how MAPK and PI3K/AKT signalling cooperate may improve molecular risk assessment, support more precise use of targeted therapies, and ultimately advance personalised care for patients with aggressive or therapy-resistant thyroid cancer.

Article: The dual axis of tumorigenesis: MAPK and PI3K/AKT pathways in papillary thyroid carcinoma

Source: Impact Journals LLC