Combination of Selpercatinib and Trametinib Overcomes Resistance to RET Inhibitors in RET-Mutant Medullary Thyroid Carcinoma. JCO Precis Oncol 2026 Jun;10(6):e2600091
Date
06/08/2026Pubmed ID
42258786Pubmed Central ID
PMC13258109DOI
10.1200/PO-26-00091Scopus ID
2-s2.0-105042355989 (requires institutional sign-in at Scopus site)Abstract
PURPOSE: Medullary thyroid carcinoma (MTC) is often driven by activating mutations in the RET receptor tyrosine kinase. Multikinase and selective inhibitors targeting RET are highly effective for RET-mutant MTC, but acquired resistance is commonly observed, limiting clinical efficacy.
MATERIALS AND METHODS: We performed a comprehensive genomic and pharmacological analysis of acquired resistance in a previously described in vitro model of RET-mutant MTC generated from long-term treatment with the RET inhibitor vandetanib. Molecular studies using spectral karyotyping, multiplex interphase fluorescence in situ hybridization, whole-exome sequencing, and RNA sequencing revealed several mechanisms of acquired resistance. Whole-genome CRISPR knockout screening was performed to identify potential genes mediating intrinsic resistance. High-throughput drug screening was used to identify additional therapeutic targets. The combination of RET and MEK inhibitors was evaluated in preclinical animal models.
RESULTS: Genomic profiling revealed that resistant MTC cells acquired RET copy-number gain and the clinically observed secondary RET mutation p.G810S. Whole-genome CRISPR knockout screening on MTC cells treated with two different RET inhibitors highlighted that NF1 deletion and subsequent RAS/MAPK activation were sufficient to establish resistance to RET inhibition. High-throughput drug screening also indicated that MTC cells are sensitive to RAS/MAPK inhibition, particularly in combination with RET inhibitors. The combination of RET and MEK inhibitors was synergistic in both RET-inhibitor-naïve and resistant MTC in mouse xenograft models.
CONCLUSION: Resistance to RET inhibitors can be acquired through RET copy-number gain and secondary mutations as well as NF1 loss-mediated MAPK pathway activation. This mechanism of resistance can be overcome with dual inhibition of RET and downstream RAS/MAPK signaling, demonstrating clinical potential in RET-mutant MTC.
Author List
Milewski D, Fallatah A, Groff M, Rahmy A, Khan SR, Okafor C, Glassberg B, Chou HC, Heselmeyer-Haddad K, Wangsa D, Wangsa D, Kim Y, Isanogle K, Song Y, Zhang X, Thomas C, Difilippantonio S, Park JI, Wei JS, Hawley RG, Glod J, Khan JMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Combined Chemotherapy Protocols
Carcinoma, Neuroendocrine
Cell Line, Tumor
Drug Resistance, Neoplasm
Humans
Mice
Mutation
Piperidines
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-ret
Pyrazoles
Pyridines
Pyridones
Pyrimidinones
Thyroid Neoplasms
