{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:46:05Z","timestamp":1787021165038,"version":"build-2736575974"},"reference-count":44,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"6","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precis Oncol"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>PURPOSE<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MATERIALS AND METHODS<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>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\u2013na\u00efve and resistant MTC in mouse xenograft models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>Resistance to RET inhibitors can be acquired through RET copy-number gain and secondary mutations as well as NF1 loss\u2013mediated 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1200\/po-26-00091","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T20:00:12Z","timestamp":1780948812000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Combination of Selpercatinib and Trametinib Overcomes Resistance to RET Inhibitors in RET-Mutant Medullary Thyroid Carcinoma"],"prefix":"10.1200","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9778-8548","authenticated-orcid":true,"given":"David","family":"Milewski","sequence":"first","affiliation":[{"name":"Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arwa","family":"Fallatah","sequence":"additional","affiliation":[{"name":"Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD"},{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD"},{"name":"Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD"},{"name":"Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, The Henry M. 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