ArticleBritish journal of pharmacology2018
Drug resistance profiles of mutations in the RET kinase domain.
Article in British journal of pharmacology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 91 citations in OpenAlex.
- Combination of Selpercatinib and Trametinib Overcomes Resistance to RET Inhibitors in RET-Mutant Medullary Thyroid Carcinoma.JCO precision oncology · 2026Article
- RET Signaling Pathway in Human Cancer: Oncogenic Mechanisms, Selective Inhibitors, and Emerging Resistance Strategies.International journal of molecular sciences · 2026Review
- Article
- Systematic evaluation of computational tools to predict the effects of mutations on protein-ligand binding affinity in the absence of experimental structures.Briefings in bioinformatics · 2026Article
- Modeling the Effects of Single Nucleotide Polymorphisms (SNPs) on the Structure and Function of the HumanHuman mutation · 2026Article
- How to manage medullary thyroid carcinoma: current treatment strategies.Drugs in context · 2026Review
- Identification of alkynyl nicotinamide HSN748 as a RET solvent-front mutant inhibitor with intracranial efficacy.RSC medicinal chemistry · 2025Article
- Mechanisms of resistance to RET-directed therapies.Endocrine-related cancer · 2025Review
- Targeting Oncogenic RET Kinase by Simultaneously Inhibiting Kinase Activity and Degrading the Protein.Journal of medicinal chemistry · 2025Article
- Article
- Overview of management and therapeutic advances in medullary thyroid cancer.Endocrine oncology (Bristol, England) · 2025Review
- First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors.Signal transduction and targeted therapy · 2024Article
- Molecular genetics, therapeutics and RET inhibitor resistance for medullary thyroid carcinoma and future perspectives.Cell communication and signaling : CCS · 2024Review
- Review
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- Review
- Discovery of 9H-pyrimido[4,5-b]indole derivatives as dual RET/TRKA inhibitors.Bioorganic & medicinal chemistry · 2024Article
- Molecular Basis and Natural History of Medullary Thyroid Cancer: It is (Almost) All in theCancers · 2023Review
- A mutation-induced drug resistance database (MdrDB).Communications chemistry · 2023Article
- Small Molecule Inhibitors as Therapeutic Agents Targeting Oncogenic Fusion Proteins: Current Status and Clinical.Molecules (Basel, Switzerland) · 2023Review
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
background and purposeAlterations in the tyrosine kinase enzyme RET are found in thyroid and lung cancer. While RET TK inhibitors (TKIs) are used to treat thyroid cancer and are in clinical trials for RET fusion-positive non-small cell lung cancer, the impact of mutations in the RET kinase domain on drug sensitivity is largely uncharacterized. EXPERIMENTAL APPROACH: We identified and analysed mutations in the RET kinase domain that conferred resistance to the TKIs cabozantinib, lenvatinib, vandetanib and nintedanib using RET kinase-dependent BaF3/KIF5B-RET (BaF3/KR) cells. We also examined the sensitivity of RET (M918T), a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B, to these TKIs in the context of BaF3/KR cells. KEY
resultsFourteen mutations were analysed. Pan resistance to the four TKIs was found in six RET kinase domain mutations (L730I, V738A, V804L/M, Y806N, G810S). Seven RET kinase domain mutations (L730V, E732K, A807V, G810A, V871I, M918T, F998V) displayed selective resistance to one or more of these drugs. L730I/V and G810A/S had different drug resistance profiles. V871I, M918T and F998V mutations are located at distant sites away from the TKI binding pocket. CONCLUSIONS AND IMPLICATIONS: A panel of TKI-resistant RET mutations were identified, and their drug sensitivities were cross-profiled. The results provide a reference for selecting appropriate TKIs to inhibit RET kinase domain mutants. Besides changes in the drug-interacting residues, mutations at distant sites could exert long-range effects resulting in TKI resistance. Among the four TKIs analysed here, nintedanib remained unaffected by mutations at the three distant sites.
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