Jul 2026· Critical reviews in oncology/hematology· Vol 226, pp.
105506
· 0 citations· 103 references
Medicine
TL;DR
An overview of the molecular mechanisms of RET alterations in thyroid cancer, targeted therapies, and emerging resistance to targeted treatment is provided.
Abstract
RET alterations, including RET fusions and RET mutations, have been identified in thyroid cancer. RET fusions are predominantly found in papillary thyroid carcinoma, whereas RET mutations are primarily associated with medullary thyroid carcinoma. Consequently, RET has emerged as an attractive therapeutic target. Previously, multikinase inhibitors, such as vandetanib and cabozantinib, were primarily used for treatment; however, their efficacy was limited due to off-target effects. Recently, selective tyrosine kinase inhibitors, including selpercatinib and pralsetinib, have been introduced, demonstrating improved selectivity and clinical efficacy. Nevertheless, challenges such as gatekeeper and solvent-front mutations have emerged, contributing to acquired drug resistance. To address this issue, next-generation RET inhibitors, including zeteletinib and SYHA1815, are currently under investigation, reflecting an expanding therapeutic landscape. This article provides an overview of the molecular mechanisms of RET alterations in thyroid cancer, targeted therapies, and emerging resistance to targeted treatment.
Abstract Background Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that contributes disproportionately to thyroid cancer–related mortality. Historically, systemic treatment options for advanced MTC were limited due to poor responsiveness to radioactive iodine and conventional chemotherapy. The development of targeted therapies has significantly transformed disease management. Methods This narrative review summarizes current evidence on targeted therapies for advanced MTC, including multikinase inhibitors (MKIs), selective RET inhibitors, and emerging treatment strategies. Literature on efficacy, safety, resistance mechanisms, and novel therapeutic approaches was evaluated. Results First-generation MKIs, including vandetanib and cabozantinib, demonstrated clinical benefit by targeting RET and angiogenic pathways, though off-target toxicities limited tolerability. More recently, selective RET inhibitors, such as selpercatinib and pralsetinib, have shown high response rates and improved safety profiles, establishing them as preferred first-line therapies for RET-mutant MTC. However, pralsetinib’s recent market withdrawal due to regulatory challenges highlights the need for additional options. Emerging therapies, including BOS172738, SY-5007, and peptide receptor radionuclide therapy, show promising early results. Resistance mechanisms, including gatekeeper and solvent front mutations, remain a challenge. Advances in clinical biomarkers and novel approaches, such as CAR-T cell therapy, may further support personalized treatment. Conclusion Targeted therapies have reshaped the management of advanced MTC, with selective RET inhibitors offering improved efficacy and tolerability. Continued research is essential to overcome resistance, expand therapeutic options, and improve patient outcomes.
H. Arain, Azeem Izhar, Rachael Caretti et al.· The Oncologist· 0 citations
Collectively, the advances are an indication of a transition to the personalized, mechanism-driven treatment strategies that would prolong the survivability of patients with advanced thyroid cancer, conquer resistance, and reduce systemic toxicity.
Tanmoy Sarkar, Ruhi Arisha, S. Sengupta et al.· Clinical and Translational O...· 0 citations
This review underscores the transformative potential of molecular profiling and FGFR-targeted therapies in the evolving management of bladder cancer, with special attention given to the fibroblast growth factor receptor (FGFR) signaling pathway.
Nandita Yadav, Nihar Ranjan Sarmah, Ketan J. Purohit et al.· Current Pharmacogenomics and...· 0 citations
ABSTRACT Introduction The discovery of epidermal growth factor receptor (EGFR) mutations has deeply reshaped the treatment of non-small cell lung cancer (NSCLC). Throughout the last years, third-generation tyrosine kinase inhibitor (TKI) osimertinib in monotherapy has been the standard of care; however, resistance limits durable responses, necessitating novel combinations and sequencing strategies. Areas covered This review discusses recent advances in EGFR-targeted therapies within the molecular landscape of classical and uncommon EGFR mutations, focusing on frontline intensification strategies in metastatic disease—specifically TKI combinations with chemotherapy (FLAURA2) or bispecific antibodies (MARIPOSA)—and emerging post-progression strategies to overcome acquired resistance mechanisms. A comprehensive literature search (January 2021–March 2026) was conducted via PubMed, and recent major oncology conference proceedings (ASCO, ESMO, WCLC, ELCC) and clinical trial registries for ongoing studies. Expert opinion The therapeutic landscape is shifting from a uniform frontline TKI monotherapy approach toward biomarker-driven, risk-stratified, intensification. High-risk patients (e.g. TP53 co-mutations, L858R) derive significant benefit from combination regimens, whereas mono-TKI remains appropriate for favorable prognostic subgroups. Future progress relies on validating predictive biomarkers—particularly circulating tumor DNA (ctDNA) dynamics—to guide adaptive treatment strategies, balancing efficacy gains against toxicity and costs, while ensuring equitable global access to novel therapies.
L. Lucente, Lucrezia Barcellini, B. Ramella Pollone et al.· Expert Opinion on Pharmacoth...· 0 citations
This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision-making and further research in this field.
Xizhi Zha· Theoretical and Natural Scie...· 0 citations
Acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a formidable challenge in the treatment of non-small cell lung cancer (NSCLC). Despite the remarkable efficacy of these agents, resistance inevitably develops, typically within approximately 10 months of treatment initiation. This review elucidates the multifaceted mechanisms driving this resistance, broadly categorized into on-target EGFR-dependent alterations and off-target EGFR-independent bypass pathway activations. On-target mechanisms include the emergence of tertiary EGFR mutations, most notably C797S, which disrupts TKI binding. Off-target mechanisms encompass the activation of alternative signaling pathways such as MET and HER2/HER3 amplification, as well as histological transformations and complex changes within the tumor microenvironment. Furthermore, recent discoveries highlight the role of epigenetic dysregulation and metabolic reprogramming in fostering resistance. To counter this pervasive adaptability, advanced diagnostic methodologies, including liquid biopsy and high-resolution omics technologies, are crucial for real-time molecular profiling. The field is actively exploring emerging combination therapeutic strategies to circumvent these diverse resistance pathways, aiming to prolong clinical benefits and improve patient outcomes. The persistent emergence of resistance underscores that current targeted therapies, while revolutionary, are primarily disease-modifying rather than curative, necessitating continuous innovation to overcome the inherent biological challenge of tumor adaptability and heterogeneity.
Gu-Ha A-Lai, Lian Li, G. Ma et al.· Frontiers in Cell and Develo...· 0 citations
