{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:48:42Z","timestamp":1790142522377,"version":"4.0.1"},"reference-count":121,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T00:00:00Z","timestamp":1744416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thyroid cancer prevalence has increased in the last few decades. Whereas the majority of well-differentiated histotypes have effective therapeutic options, the most advanced cases lacked successful treatment until recent years. Genomic alterations have emerged as targets for new anti-cancer drugs. This molecular knowledge is gradually being translated into sophisticated approaches for the stratification, management, and therapies of patients with thyroid carcinomas. The genomic characterisation of tumours in clinical assistance serves as a tool for enhancing the prognostic assessment of patients with thyroid cancer and predicting their responses to the agents. The MAPK pathway is the most predominantly activated molecular route in this cancer. Several drugs have been developed to inhibit this pathway at different levels. However, the acquired resistance that emerges is the main problem in their use. Other strategies targeting not only driver mutations but also those that confer aggressive behaviour on tumours can be potential targetable options. Due to the new therapies, patients with the most aggressive histotypes have improved survival rates. Adverse events, although manageable, have a high prevalence among the current therapies. Selective inhibitors, immunotherapies, and the combination of both will play a pivotal role in the treatment and the improvements in overall survival in thyroid cancer patients.<\/jats:p>","DOI":"10.3390\/ijms26083663","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T06:18:36Z","timestamp":1744611516000},"page":"3663","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Revolution of Targeted Therapies in Thyroid Cancer Treatment: Present and Future Promising Anti-Cancer Drugs"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0199-6893","authenticated-orcid":false,"given":"Sara","family":"Gil-Bernab\u00e9","sequence":"first","affiliation":[{"name":"Pathology Department, Faculty of Medicine, Valladolid University, 47003 Valladolid, Spain"},{"name":"Group Pathobiology of Cancer: Inter-, Intra-Tumor Heterogeneity and Molecular Targets, Institute of Molecular Genetics and Biomedicine (IBGM), 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Garc\u00eda-DeLaFuente","sequence":"additional","affiliation":[{"name":"Pathology Department, Faculty of Medicine, Valladolid University, 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginesa","family":"Garc\u00eda-Rost\u00e1n","sequence":"additional","affiliation":[{"name":"Pathology Department, Faculty of Medicine, Valladolid University, 47003 Valladolid, Spain"},{"name":"Group Pathobiology of Cancer: Inter-, Intra-Tumor Heterogeneity and Molecular Targets, Institute of Molecular Genetics and Biomedicine (IBGM), 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1016\/S0140-6736(16)30172-6","article-title":"Thyroid Cancer","volume":"388","author":"Cabanillas","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1001\/jama.2023.26348","article-title":"Thyroid Cancer: A Review","volume":"331","author":"Boucai","year":"2024","journal-title":"JAMA"},{"key":"ref_3","unstructured":"WHO Classification of Tumours Series (2022). WHO Classification of Tumours Editorial Board. Endocrine and Neuroendocrine Tumours."},{"key":"ref_4","unstructured":"Cancer Genome Atlas Research Network (2014). Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell, 159, 676\u2013690."},{"key":"ref_5","first-page":"e220293","article-title":"The 2022 WHO Classification of Thyroid Tumors: Novel Concepts in Nomenclature and Grading","volume":"30","author":"Juhlin","year":"2023","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1172\/JCI85271","article-title":"Genomic and Transcriptomic Hallmarks of Poorly Differentiated and Anaplastic Thyroid Cancers","volume":"126","author":"Landa","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113826","DOI":"10.1016\/j.celrep.2024.113826","article-title":"The Genomic and Evolutionary Landscapes of Anaplastic Thyroid Carcinoma","volume":"43","author":"Zeng","year":"2024","journal-title":"Cell Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1089\/thy.2014.0335","article-title":"Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma","volume":"25","author":"Wells","year":"2015","journal-title":"Thyroid"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3892\/ol.2010.223","article-title":"Medullary Thyroid Carcinoma: The Third Most Common Thyroid Cancer Reviewed","volume":"2","author":"Stamatakos","year":"2011","journal-title":"Oncol. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1210\/er.2019-00007","article-title":"Targeted Therapy for Advanced Thyroid Cancer: Kinase Inhibitors and Beyond","volume":"40","author":"Cabanillas","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41574-023-00920-6","article-title":"Genomic Alterations in Thyroid Cancer: Biological and Clinical Insights","volume":"20","author":"Landa","year":"2024","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"102039","DOI":"10.1016\/j.esmoop.2023.102039","article-title":"Clinical Relevance of Gene Mutations and Rearrangements in Advanced Differentiated Thyroid Cancer","volume":"8","author":"Nannini","year":"2023","journal-title":"ESMO Open"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sahakian, N., Castinetti, F., and Romanet, P. (2023). Molecular Basis and Natural History of Medullary Thyroid Cancer: It Is (Almost) All in the RET. Cancers, 15.","DOI":"10.3390\/cancers15194865"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/s41392-023-01705-z","article-title":"Targeting the RAS\/RAF\/MAPK Pathway for Cancer Therapy: From Mechanism to Clinical Studies","volume":"8","author":"Bahar","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3175","DOI":"10.1038\/s41467-024-47581-1","article-title":"Integrated Proteogenomic and Metabolomic Characterization of Papillary Thyroid Cancer with Different Recurrence Risks","volume":"15","author":"Qu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Prete, A., Borges de Souza, P., Censi, S., Muzza, M., Nucci, N., and Sponziello, M. (2020). Update on Fundamental Mechanisms of Thyroid Cancer. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00102"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1200\/JCO.2014.56.8253","article-title":"Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer","volume":"33","author":"Xing","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1530\/ERC-13-0399","article-title":"Histone Deacetylation of NIS Promoter Underlies BRAF V600E-Promoted NIS Silencing in Thyroid Cancer","volume":"21","author":"Zhang","year":"2014","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"104570","DOI":"10.1016\/j.amjoto.2024.104570","article-title":"Decoding RAS Mutations in Thyroid Cancer: A Meta-Analysis Unveils Specific Links to Distant Metastasis and Increased Mortality","volume":"46","author":"Riccio","year":"2025","journal-title":"Am. J. Otolaryngol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1634\/theoncologist.2013-0072","article-title":"RAS Mutations in Thyroid Cancer","volume":"18","author":"Howell","year":"2013","journal-title":"Oncologist"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1158\/1078-0432.CCR-23-0278","article-title":"Additional Oncogenic Alterations in RAS-Driven Differentiated Thyroid Cancers Associate with Worse Clinicopathologic Outcomes","volume":"29","author":"Bikas","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1586\/14737140.8.4.625","article-title":"RET Oncogene in MEN2, MEN2B, MTC, and Other Forms of Thyroid Cancer: Molecular Genetics and Therapeutic Advances","volume":"8","author":"Lodish","year":"2008","journal-title":"Expert. Rev. Anticancer Ther."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Santoro, M., Moccia, M., Federico, G., and Carlomagno, F. (2020). RET Gene Fusions in Malignancies of the Thyroid and Other Tissues. Genes, 11.","DOI":"10.3390\/genes11040424"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.semcancer.2021.03.035","article-title":"Multiple Endocrine Neoplasia Type 2: A Review","volume":"79","author":"Mathiesen","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"514","DOI":"10.3803\/EnM.2021.1082","article-title":"Current Guidelines for Management of Medullary Thyroid Carcinoma","volume":"36","author":"Kim","year":"2021","journal-title":"Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E754","DOI":"10.1210\/jc.2013-3734","article-title":"TERT Promoter Mutations Are a Major Indicator of Poor Outcome in Differentiated Thyroid Carcinomas","volume":"99","author":"Melo","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R143","DOI":"10.1530\/ERC-15-0533","article-title":"TERT Promoter Mutations in Thyroid Cancer","volume":"23","author":"Liu","year":"2016","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1530\/ERC-13-0210","article-title":"Highly Prevalent TERT Promoter Mutations in Aggressive Thyroid Cancers","volume":"20","author":"Liu","year":"2013","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Mabeta, P., and Steenkamp, V. (2022). The VEGF\/VEGFR Axis Revisited: Implications for Cancer Therapy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415585"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.ejmech.2015.12.016","article-title":"Recent Advances in the Development of Dual VEGFR and C-Met Small Molecule Inhibitors as Anticancer Drugs","volume":"108","author":"Zhang","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bandargal, S., Chen, T., Pusztaszeri, M.P., Forest, V.-I., da Silva, S.D., and Payne, R.J. (2022). Prognostic Indicators of EIF1AX-Mutated Thyroid Tumor Malignancy and Cancer Aggressiveness. Cancers, 14.","DOI":"10.3390\/cancers14246097"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1530\/ERC-16-0043","article-title":"Prevalence and Phenotypic Correlations of EIF1AX Mutations in Thyroid Nodules","volume":"23","author":"Karunamurthy","year":"2016","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0378-1119(99)00210-3","article-title":"Initiation of Translation in Prokaryotes and Eukaryotes","volume":"234","author":"Kozak","year":"1999","journal-title":"Gene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1158\/2159-8290.CD-18-0606","article-title":"EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and C-MYC","volume":"9","author":"Krishnamoorthy","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"bqad118","DOI":"10.1210\/endocr\/bqad118","article-title":"Mechanistic Insights of Thyroid Cancer Progression","volume":"164","author":"Landa","year":"2023","journal-title":"Endocrinology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/nrendo.2011.141","article-title":"Multikinase Inhibitors: A New Option for the Treatment of Thyroid Cancer","volume":"7","author":"Gild","year":"2011","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7099","DOI":"10.1158\/0008-5472.CAN-04-1443","article-title":"BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF\/MEK\/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis","volume":"64","author":"Wilhelm","year":"2004","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/S0092-8674(04)00215-6","article-title":"Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF","volume":"116","author":"Wan","year":"2004","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1093\/jnci\/djj069","article-title":"BAY 43-9006 Inhibition of Oncogenic RET Mutants","volume":"98","author":"Carlomagno","year":"2006","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6861","DOI":"10.1038\/sj.onc.1208841","article-title":"The Role of Mcl-1 Downregulation in the Proapoptotic Activity of the Multikinase Inhibitor BAY 43-9006","volume":"24","author":"Yu","year":"2005","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0140-6736(14)60421-9","article-title":"Sorafenib in Radioactive Iodine-Refractory, Locally Advanced or Metastatic Differentiated Thyroid Cancer: A Randomised, Double-Blind, Phase 3 Trial","volume":"384","author":"Brose","year":"2014","journal-title":"Lancet"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1001\/jamaoncol.2015.5927","article-title":"Toxic Effects of Sorafenib in Patients With Differentiated Thyroid Carcinoma Compared With Other Cancers","volume":"2","author":"Jean","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5459","DOI":"10.1158\/1078-0432.CCR-07-5270","article-title":"Multi-Kinase Inhibitor E7080 Suppresses Lymph Node and Lung Metastases of Human Mammary Breast Tumor MDA-MB-231 via Inhibition of Vascular Endothelial Growth Factor-Receptor (VEGF-R) 2 and VEGF-R3 Kinase","volume":"14","author":"Matsui","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_44","first-page":"1457","article-title":"Autophagy Regulates Anti-Angiogenic Property of Lenvatinib in Thyroid Cancer","volume":"13","author":"Xue","year":"2023","journal-title":"Am. J. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1056\/NEJMoa1406470","article-title":"Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer","volume":"372","author":"Schlumberger","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_46","first-page":"7284","article-title":"ZD6474, an Orally Available Inhibitor of KDR Tyrosine Kinase Activity, Efficiently Blocks Oncogenic RET Kinases1","volume":"62","author":"Carlomagno","year":"2002","journal-title":"Cancer Res."},{"key":"ref_47","first-page":"4645","article-title":"ZD6474 Inhibits Vascular Endothelial Growth Factor Signaling, Angiogenesis, and Tumor Growth Following Oral Administration","volume":"62","author":"Wedge","year":"2002","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1200\/JCO.2011.35.5040","article-title":"Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial","volume":"30","author":"Wells","year":"2012","journal-title":"JCO"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1158\/1535-7163.MCT-11-0264","article-title":"Cabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor Growth","volume":"10","author":"Yakes","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"A13","DOI":"10.1158\/1535-7163.TARG-09-A13","article-title":"Abstract A13: Reduction of Tumor Invasiveness and Metastasis and Prolongation of Survival of RIP-Tag2 Mice after Inhibition of VEGFR plus c-Met by XL184","volume":"8","author":"Sennino","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1093\/annonc\/mdx479","article-title":"Overall Survival Analysis of EXAM, a Phase III Trial of Cabozantinib in Patients with Radiographically Progressive Medullary Thyroid Carcinoma","volume":"28","author":"Schlumberger","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/S1470-2045(21)00332-6","article-title":"Cabozantinib for Radioiodine-Refractory Differentiated Thyroid Cancer (COSMIC-311): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial","volume":"22","author":"Brose","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4203","DOI":"10.1002\/cncr.34493","article-title":"Cabozantinib for Previously Treated Radioiodine-Refractory Differentiated Thyroid Cancer: Updated Results from the Phase 3 COSMIC-311 Trial","volume":"128","author":"Brose","year":"2022","journal-title":"Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1056\/NEJMoa1209288","article-title":"Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer","volume":"368","author":"Ho","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1210\/jc.2018-01478","article-title":"Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers","volume":"104","author":"Dunn","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_56","first-page":"R173","article-title":"Molecular Mechanisms of Resistance to Kinase Inhibitors and Redifferentiation in Thyroid Cancers","volume":"1","author":"Hofmann","year":"2022","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"B88","DOI":"10.1158\/1535-7163.TARG-09-B88","article-title":"Abstract B88: A Selective Raf Kinase Inhibitor Induces Cell Death and Tumor Regression of Human Cancer Cell Lines Encoding B-RafV600E Mutation","volume":"8","author":"Laquerre","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/S0140-6736(12)60398-5","article-title":"Dabrafenib in Patients with Melanoma, Untreated Brain Metastases, and Other Solid Tumours: A Phase 1 Dose-Escalation Trial","volume":"379","author":"Falchook","year":"2012","journal-title":"Lancet"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Martens, U.M. (2018). Trametinib (GSK1120212). Small Molecules in Oncology, Springer International Publishing.","DOI":"10.1007\/978-3-319-91442-8"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1158\/1535-7163.MCT-11-0989","article-title":"Combinations of BRAF, MEK, and PI3K\/mTOR Inhibitors Overcome Acquired Resistance to the BRAF Inhibitor GSK2118436 Dabrafenib, Mediated by NRAS or MEK Mutations","volume":"11","author":"Greger","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.annonc.2021.12.014","article-title":"Dabrafenib plus Trametinib in Patients with BRAF V600E-Mutant Anaplastic Thyroid Cancer: Updated Analysis from the Phase II ROAR Basket Study","volume":"33","author":"Subbiah","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_62","first-page":"1184","article-title":"Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial","volume":"32","author":"Busaidy","year":"2022","journal-title":"Thyroid"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1158\/1078-0432.CCR-23-0046","article-title":"A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer","volume":"29","author":"Leboulleux","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1158\/1078-0432.CCR-14-2915","article-title":"Redifferentiation of Iodine-Refractory BRAF V600E-Mutant Metastatic Papillary Thyroid Cancer with Dabrafenib","volume":"21","author":"Rothenberg","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"A876","DOI":"10.1210\/jendso\/bvab048.1789","article-title":"MERAIODE: A Redifferentiation Phase II Trial With Trametinib and Dabrafenib Followed by Radioactive Iodine Administration for Metastatic Radioactive Iodine Refractory Differentiated Thyroid Cancer Patients With a BRAFV600E Mutation (NCT 03244956)","volume":"5","author":"Leboulleux","year":"2021","journal-title":"J. Endocr. Soc."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1016\/S1470-2045(16)30166-8","article-title":"Vemurafenib in Patients with BRAFV600E-Positive Metastatic or Unresectable Papillary Thyroid Cancer Refractory to Radioactive Iodine: A Non-Randomised, Multicentre, Open-Label, Phase 2 Trial","volume":"17","author":"Brose","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Martens, U.M. (2018). Vemurafenib. Small Molecules in Oncology, Springer International Publishing.","DOI":"10.1007\/978-3-319-91442-8"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00280-022-04437-z","article-title":"Efficacy and Toxicity of Vemurafenib and Cobimetinib in Relation to Plasma Concentrations, after Administration via Feeding Tube in Patients with BRAF-Mutated Thyroid Cancer: A Case Series and Review of Literature","volume":"90","author":"Zeverijn","year":"2022","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_69","unstructured":"Cancer Research UK (2025, February 16). DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage\/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations Treatment Arm 05: Vemurafenib in Combination With Cobimetinib in Adult Patients With BRAF Positive Cancers.; Clinical Trial Registration NCT05768178, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05768178."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1089\/thy.2019.0143","article-title":"Mitogen-Activated Protein Kinase Pathway Inhibition for Redifferentiation of Radioiodine Refractory Differentiated Thyroid Cancer: An Evolving Protocol","volume":"29","author":"Iravani","year":"2019","journal-title":"Thyroid"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.7150\/jca.83853","article-title":"Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer","volume":"14","author":"Ma","year":"2023","journal-title":"J. Cancer"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.celrep.2014.07.010","article-title":"Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors","volume":"8","author":"Sos","year":"2014","journal-title":"Cell Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1158\/2159-8290.CD-12-0531","article-title":"Relief of Feedback Inhibition of HER3 Transcription by RAF and MEK Inhibitors Attenuates Their Antitumor Effects in BRAF-Mutant Thyroid Carcinomas","volume":"3","author":"Dominguez","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s12943-022-01676-9","article-title":"Yap Governs a Lineage-Specific Neuregulin1 Pathway-Driven Adaptive Resistance to RAF Kinase Inhibitors","volume":"21","author":"Krishnamoorthy","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e226","DOI":"10.1016\/j.jtho.2018.06.021","article-title":"Emergence of a RET V804M Gatekeeper Mutation During Treatment With Vandetanib in RET-Rearranged NSCLC","volume":"13","author":"Stevens","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1093\/annonc\/mdy188","article-title":"The Right Compound for the Right Target: Tackling RET","volume":"29","author":"Seoane","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/s41467-018-02994-7","article-title":"A Secondary RET Mutation in the Activation Loop Conferring Resistance to Vandetanib","volume":"9","author":"Nakaoku","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Gil-Bernab\u00e9, S., Garc\u00eda-DeLaFuente, L., Garc\u00eda-\u00c1lvarez, A., Garc\u00eda-Rost\u00e1n, G., Capdevila, J., and Hernando, J. (2025). Genomics Review of Selective RET Inhibitors Sensitivity in Thyroid Cancer Clinical Trials. Am. J. Med. Genet. Part C Semin. Med. Genet., e32127.","DOI":"10.1002\/ajmg.c.32127"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1056\/NEJMoa2005651","article-title":"Efficacy of Selpercatinib in RET -Altered Thyroid Cancers","volume":"383","author":"Wirth","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1093\/annonc\/mdy137","article-title":"Selective RET Kinase Inhibition for Patients with RET-Altered Cancers","volume":"29","author":"Subbiah","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"S144","DOI":"10.1016\/S0959-8049(16)33028-3","article-title":"The Development of a Potent, KDR\/VEGFR2-Sparing RET Kinase Inhibitor for Treating Patients with RET-Dependent Cancers","volume":"69","author":"Brandhuber","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.jtho.2020.01.006","article-title":"RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies","volume":"15","author":"Solomon","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/S1470-2045(22)00541-1","article-title":"Tumour-Agnostic Efficacy and Safety of Selpercatinib in Patients with RET Fusion-Positive Solid Tumours Other than Lung or Thyroid Tumours (LIBRETTO-001): A Phase 1\/2, Open-Label, Basket Trial","volume":"23","author":"Subbiah","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1056\/NEJMoa2309719","article-title":"Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer","volume":"389","author":"Hadoux","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1158\/2159-8290.CD-18-0338","article-title":"Precision Targeted Therapy with BLU-667 for RET-Driven Cancers","volume":"8","author":"Subbiah","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.annonc.2020.10.599","article-title":"Structural Basis of Acquired Resistance to Selpercatinib and Pralsetinib Mediated by Non-Gatekeeper RET Mutations","volume":"32","author":"Subbiah","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S2213-8587(21)00120-0","article-title":"Pralsetinib for Patients with Advanced or Metastatic RET-Altered Thyroid Cancer (ARROW): A Multi-Cohort, Open-Label, Registrational, Phase 1\/2 Study","volume":"9","author":"Subbiah","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1089\/thy.2023.0363","article-title":"Pralsetinib in Patients with Advanced\/Metastatic Rearranged During Transfection (RET)-Altered Thyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study","volume":"34","author":"Subbiah","year":"2024","journal-title":"Thyroid"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Clark, L., Fisher, G., Brook, S., Patel, S., and Arkenau, H.-T. (2023). Selective RET Inhibitors (SRIs) in Cancer: A Journey from Multi-Kinase Inhibitors to the Next Generation of SRIs. Cancers, 16.","DOI":"10.3390\/cancers16010031"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Schoffski, P., Cho, B.C., Italiano, A., Loong, H.H.F., Massard, C., Medina Rodriguez, L., Shih, J.-Y., Subbiah, V., Verlingue, L., and Andreas, K. (2021). BOS172738, a Highly Potent and Selective RET Inhibitor, for the Treatment of RET-Altered Tumors Including RET-Fusion+ NSCLC and RET-Mutant MTC: Phase 1 Study Results. J. Clin. Oncol., 39.","DOI":"10.1200\/JCO.2021.39.15_suppl.3008"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"P06-02","DOI":"10.1158\/1535-7163.TARG-21-P06-02","article-title":"Abstract P06-02: Discovery of TAS0953\/HM06, a Novel next Generation RET-Specific Inhibitor Capable of Inhibiting RET Solvent Front Mutations","volume":"20","author":"Miyazaki","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1038\/s43018-023-00630-y","article-title":"Vepafestinib Is a Pharmacologically Advanced RET-Selective Inhibitor with High CNS Penetration and Inhibitory Activity against RET Solvent Front Mutations","volume":"4","author":"Miyazaki","year":"2023","journal-title":"Nat. Cancer"},{"key":"ref_93","unstructured":"Shouyao Holdings (Beijing), Co. LTD (2024, January 01). A Phase I\/II, Open-Label, Single-Arm, Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antineoplastic Activity of SY-5007 in Patients With RET-Altered Advanced Solid Tumor; Clinical Trial Registration NCT05278364, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05278364."},{"key":"ref_94","unstructured":"Ellipses Pharma (2025, February 18). A Modular, Open-Label, Phase I\/II Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of EP0031 in Patients With Advanced RET-Altered Malignancies; Clinical Trial Registration NCT05443126, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05443126."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/nrd2221","article-title":"Post-Translational Modifications and Regulation of the RAS Superfamily of GTPases as Anticancer Targets","volume":"6","author":"Konstantinopoulos","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"14459","DOI":"10.1074\/jbc.272.22.14459","article-title":"K- and N-Ras Are Geranylgeranylated in Cells Treated with Farnesyl Protein Transferase Inhibitors","volume":"272","author":"Whyte","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1158\/0008-5472.CAN-17-1925","article-title":"Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers","volume":"78","author":"Untch","year":"2018","journal-title":"Cancer Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"7061","DOI":"10.1158\/1078-0432.CCR-09-1241","article-title":"Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Advanced Malignancies","volume":"15","author":"Hong","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s40618-018-0947-4","article-title":"The Efficacy of HRAS and CDK4\/6 Inhibitors in Anaplastic Thyroid Cancer Cell Lines","volume":"42","author":"Pojo","year":"2019","journal-title":"J. Endocrinol. Invest."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.2174\/1871520623666230607125258","article-title":"In Silico Screening and Validation of Achyranthes Aspera as a Potential Inhibitor of BRAF and NRAS in Controlling Thyroid Cancer","volume":"23","author":"Alamri","year":"2023","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Turner, N., Hamidi, S., Ouni, R., Rico, R., Henderson, Y.C., Puche, M., Alekseev, S., Colunga-Minutti, J.G., Zafereo, M.E., and Lai, S.Y. (2024). Emerging Therapeutic Options for Follicular-Derived Thyroid Cancer in the Era of Immunotherapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1369780"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/s41571-018-0113-0","article-title":"NTRK Fusion-Positive Cancers and TRK Inhibitor Therapy","volume":"15","author":"Cocco","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/s12032-023-02063-0","article-title":"Evaluation of the Anticancer Effect of Telomerase Inhibitor BIBR1532 in Anaplastic Thyroid Cancer in Terms of Apoptosis, Migration and Cell Cycle","volume":"40","author":"Turkmen","year":"2023","journal-title":"Med. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1021\/acs.jmedchem.3c01708","article-title":"Lead Optimization of BIBR1591 To Improve Its Telomerase Inhibitory Activity: Design and Synthesis of Novel Four Chemical Series with In Silico, In Vitro, and In Vivo Preclinical Assessments","volume":"67","author":"Mousa","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13073-016-0324-x","article-title":"Roles of Telomeres and Telomerase in Cancer, and Advances in Telomerase-Targeted Therapies","volume":"8","author":"Jafri","year":"2016","journal-title":"Genome Med."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Wang, X., Gao, Z., Liu, Y., Wang, P., Fang, X., Sun, M., Ma, K., Wang, B., and Han, W. (2025). Design and Synthesis of Novel Structures with Anti-Tumor Effects: Targeting Telomere G-Quadruplex and hTERT. Bioorganic Med. Chem. Lett., 118.","DOI":"10.1016\/j.bmcl.2024.130083"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"13363","DOI":"10.1021\/acs.jmedchem.4c01255","article-title":"Targeting hTERT Promoter G-Quadruplex DNA Structures with Small-Molecule Ligand to Downregulate hTERT Expression for Triple-Negative Breast Cancer Therapy","volume":"67","author":"Long","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ejphar.2017.03.034","article-title":"A Harmine-Derived Beta-Carboline Displays Anti-Cancer Effects in Vitro by Targeting Protein Synthesis","volume":"805","author":"Carvalho","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Mehnert, J.M., Varga, A., Brose, M.S., Aggarwal, R.R., Lin, C.-C., Prawira, A., de Braud, F., Tamura, K., Doi, T., and Piha-Paul, S.A. (2019). Safety and Antitumor Activity of the Anti\u2013PD-1 Antibody Pembrolizumab in Patients with Advanced, PD-L1\u2013Positive Papillary or Follicular Thyroid Cancer. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5380-3"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1002\/cncr.34657","article-title":"Efficacy and Safety of Pembrolizumab Monotherapy in Patients with Advanced Thyroid Cancer in the Phase 2 KEYNOTE-158 Study","volume":"129","author":"Oh","year":"2023","journal-title":"Cancer"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1089\/thy.2020.0322","article-title":"Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma","volume":"31","author":"Dierks","year":"2021","journal-title":"Thyroid"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.1158\/1078-0432.CCR-23-3417","article-title":"Combination Targeted Therapy with Pembrolizumab and Lenvatinib in Progressive, Radioiodine-Refractory Differentiated Thyroid Cancers","volume":"30","author":"French","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1089\/thy.2023.0573","article-title":"Checkpoint Inhibition in Addition to Dabrafenib\/Trametinib for BRAFV600E-Mutated Anaplastic Thyroid Carcinoma","volume":"34","author":"Hamidi","year":"2024","journal-title":"Thyroid"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e000530","DOI":"10.1136\/jitc-2020-000530","article-title":"A First-in-Human Phase 1 Dose Escalation Study of Spartalizumab (PDR001), an Anti\u2013PD-1 Antibody, in Patients with Advanced Solid Tumors","volume":"8","author":"Naing","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1200\/JCO.19.02727","article-title":"PD-1 Blockade in Anaplastic Thyroid Carcinoma","volume":"38","author":"Capdevila","year":"2020","journal-title":"J. Clin. Oncol"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1080\/19420862.2015.1136043","article-title":"Preclinical Pharmacokinetics, Pharmacodynamics, Tissue Distribution, and Tumor Penetration of Anti-PD-L1 Monoclonal Antibody, an Immune Checkpoint Inhibitor","volume":"8","author":"Deng","year":"2016","journal-title":"mAbs"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1158\/1078-0432.CCR-16-1417","article-title":"Atezolizumab: A PD-L1\u2013Blocking Antibody for Bladder Cancer","volume":"23","author":"Inman","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1001\/jamaoncol.2024.4729","article-title":"Anti\u2013Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma: A Nonrandomized Clinical Trial","volume":"10","author":"Cabanillas","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1007\/s00405-024-08965-7","article-title":"Comparison of Prognosis between Oncocytic Thyroid Carcinoma and Follicular Thyroid Carcinoma: A Population-Based Propensity Score Matching Analysis","volume":"282","author":"Peng","year":"2025","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s12672-024-01677-8","article-title":"Nanomedicine Mediated Thyroid Cancer Diagnosis and Treatment: An Approach from Generalized to Personalized Medicine","volume":"15","author":"Gulwani","year":"2024","journal-title":"Discov. Oncol."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Greco, A., Coperchini, F., Croce, L., Magri, F., Teliti, M., and Rotondi, M. (2023). Drug Repositioning in Thyroid Cancer Treatment: The Intriguing Case of Anti-Diabetic Drugs. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1303844"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3663\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:13:25Z","timestamp":1760030005000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3663"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,12]]},"references-count":121,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26083663"],"URL":"https:\/\/doi.org\/10.3390\/ijms26083663","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,12]]}}}