{"entity":{"id":"ret","kind":"target","name":"RET","aka":[],"tldr":"RET is a kinase altered in thyroid cancer and a small slice of lung cancer, treatable with one selective pill regardless of where the tumour is.","summary":"RET is the receptor tyrosine kinase for GDNF-family ligands, and cancers can switch it on either through gene fusions or point mutations. RET fusions occur in about 1 to 2 percent of NSCLC and in roughly 10 to 20 percent of papillary thyroid cancers, while RET mutations drive around 60 to 70 percent of medullary thyroid cancers. The selective inhibitors selpercatinib and pralsetinib produce responses in all of these settings, and selpercatinib holds a tumour-agnostic approval for RET-fusion solid tumours, with expanded labels in 2026. Selective inhibitors largely replaced older multikinase drugs such as vandetanib and cabozantinib because they are better tolerated. Acquired resistance through solvent-front mutations and the role of next-generation inhibitors are the open questions. For a newcomer: RET is a kinase treatable with one selective pill wherever the tumour is.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/RET_proto-oncogene","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/RET_proto-oncogene"}],"tags":["driver","kinase"],"related":["ret-fusion"],"cancers":["thyroid","nsclc","colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["guardant360-cdx","oncomine-dx-target-test","al2846","ep0031"],"companies":["imagene-ai","lucence"],"institutions":[],"pathways":["ras-mapk","nsclc-signalling","thyroid-cancer-signalling"],"terms":["gene-fusion","tumour-agnostic"],"trials":["nct06147570"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Colorectal cancer: RET fusions (NCOA4-RET, CCDC6-RET) in about 0.1% of tumours (cBioPortal), again clustered in the wild-type, mismatch repair deficient, right-sided corner. Selpercatinib's approval for RET fusion-positive solid tumours is tumour-agnostic; the colorectal evidence is a handful of patients.","Lung cancer: rearranged in 1 to 2% of adenocarcinomas, with KIF5B the dominant partner and CCDC6 second (cBioPortal), the reverse of thyroid cancer. Like the other fusions it needs an assay that reads rearrangements rather than exons."],"symbol":"RET","role":[],"sources":[],"specificity":"tumour-specific","distribution":"many-types","tumourAgnostic":true,"specificityNote":"Tumour-specific alteration: 1 of 1 label readouts filed under it measure a sequence variant (RET fusion and RET mutation) absent from normal cells. HPA RET: RNA tissue enhanced (adrenal gland 11 nTPM, parathyroid gland 19 nTPM); high antibody staining in 2 normal tissues; highest cancer staining melanoma (6 of 8 high). Distribution: 2 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Thyroid cancer, Lung cancer (all types)); Open Targets associates it with 17 specific cancer types at or above 0.5 (multiple endocrine neoplasia type 2A, medullary thyroid gland carcinoma, multiple endocrine neoplasia type 2B, pheochromocytoma, multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma and more). Tissue-agnostic: Selpercatinib US 2022: \"RET-fusion solid tumours (tumour-agnostic)\". (Rule 3 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"RET fusion and RET mutation label threshold","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=16edd46e-28b8-f06d-e063-6394a90ae31b","note":"RET fusion-positive"},{"label":"Human Protein Atlas RET tissue","url":"https://www.proteinatlas.org/ENSG00000165731-RET/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000165731 associations","url":"https://platform.opentargets.org/target/ENSG00000165731/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:9967","ensembl":"ENSG00000165731","uniprot":"P07949","entrez":"5979","firstDescribed":1987,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Takahashi et al, Mol. Cell. Biol, 1987, \"ret transforming gene encodes a fusion protein homologous to tyrosine kinases\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/3037315/","biology":"RET is the receptor tyrosine kinase for GDNF-family ligands.","whereFound":["Medullary thyroid cancer","Papillary thyroid cancer","NSCLC","Colorectal cancer: gene fusion (ncoa4-ret, ccdc6-ret) 0.1%","Non-small-cell lung cancer: rearrangement, commonly kif5b-ret or ccdc6-ret 1-2%"],"targetClass":"kinase","prevalence":[{"cancerId":"thyroid","pct":"60-70","measure":"RET mutation in medullary thyroid cancer","source":"https://en.wikipedia.org/wiki/RET_proto-oncogene","note":"~10-20% RET fusions in papillary"},{"cancerId":"nsclc","pct":"1-2","measure":"Fusion","source":"https://www.cbioportal.org/study/summary?id=luad_tcga_pan_can_atlas_2018"},{"cancerId":"colorectal","pct":"0.1","measure":"Gene fusion (NCOA4-RET, CCDC6-RET)","source":"https://www.cbioportal.org/study/summary?id=crc_msk_2026","note":"cBioPortal structural variants: 8 of 7,237, 0.11% (NCOA4-RET 4), in crc_msk_2026; 1 of 1,134 in crc_msk_2017; CCDC6-RET in 1 of 594 in coadread_tcga_pan_can_atlas_2018; 1 of 1,516 in crc_eo_2020."},{"cancerId":"nsclc","pct":"1-2","measure":"Rearrangement, commonly KIF5B-RET or CCDC6-RET","source":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2023_met_organotropism","note":"cBioPortal structural variants: 51 of 2,422, 2.1%, in luad_mskcc_2023_met_organotropism (KIF5B in 36 events, CCDC6 in 4); 38 of 2,621, 1.4%, in nsclc_ctdx_msk_2022; 16 of 915, 1.7%, in lung_msk_2017; 3 of 232, 1.3%, in lung_nci_2022."}]},"route":"/targets/ret/","neighbours":{"biomarker":[{"id":"ret-fusion","kind":"biomarker","name":"RET fusion and RET mutation","route":"/biomarkers/ret-fusion/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"hereditary-ppgl","kind":"cancer","name":"Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)","route":"/cancers/hereditary-ppgl/"},{"id":"inflammatory-myofibroblastic-tumour","kind":"cancer","name":"Inflammatory myofibroblastic tumour (IMT)","route":"/cancers/inflammatory-myofibroblastic-tumour/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"medullary-thyroid-cancer","kind":"cancer","name":"Medullary thyroid cancer","route":"/cancers/medullary-thyroid-cancer/"},{"id":"multiple-endocrine-neoplasia","kind":"cancer","name":"Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)","route":"/cancers/multiple-endocrine-neoplasia/"},{"id":"men2-syndrome","kind":"cancer","name":"Multiple endocrine neoplasia type 2 (MEN2A and MEN2B)","route":"/cancers/men2-syndrome/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"pheochromocytoma-paraganglioma","kind":"cancer","name":"Pheochromocytoma and paraganglioma (PPGL)","route":"/cancers/pheochromocytoma-paraganglioma/"},{"id":"ret-fusion-nsclc","kind":"cancer","name":"RET fusion-positive non-small-cell lung cancer","route":"/cancers/ret-fusion-nsclc/"},{"id":"thyroid","kind":"cancer","name":"Thyroid cancer","route":"/cancers/thyroid/"}],"drug":[{"id":"al2846","kind":"drug","name":"AL2846","route":"/drugs/al2846/"},{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"ep0031","kind":"drug","name":"EP0031","route":"/drugs/ep0031/"},{"id":"guardant360-cdx","kind":"drug","name":"Guardant360 CDx","route":"/drugs/guardant360-cdx/"},{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"},{"id":"oncomine-dx-target-test","kind":"drug","name":"Oncomine Dx Target Test","route":"/drugs/oncomine-dx-target-test/"},{"id":"pralsetinib","kind":"drug","name":"Pralsetinib","route":"/drugs/pralsetinib/"},{"id":"regorafenib","kind":"drug","name":"Regorafenib","route":"/drugs/regorafenib/"},{"id":"selpercatinib","kind":"drug","name":"Selpercatinib","route":"/drugs/selpercatinib/"},{"id":"vandetanib","kind":"drug","name":"Vandetanib","route":"/drugs/vandetanib/"}],"company":[{"id":"imagene-ai","kind":"company","name":"Imagene AI","route":"/companies/imagene-ai/"},{"id":"lucence","kind":"company","name":"Lucence","route":"/companies/lucence/"}],"pathway":[{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"},{"id":"thyroid-cancer-signalling","kind":"pathway","name":"Thyroid cancer (KEGG map)","route":"/pathways/thyroid-cancer-signalling/"}],"term":[{"id":"gene-fusion","kind":"term","name":"Gene fusion","route":"/terms/gene-fusion/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"trial":[{"id":"nct06147570","kind":"trial","name":"A Study of HS-10365 in Patients With Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer","route":"/trials/nct06147570/"},{"id":"arrow-thyroid","kind":"trial","name":"ARROW (thyroid cohorts)","route":"/trials/arrow-thyroid/"},{"id":"libretto-431","kind":"trial","name":"LIBRETTO-431","route":"/trials/libretto-431/"},{"id":"libretto-531","kind":"trial","name":"LIBRETTO-531","route":"/trials/libretto-531/"},{"id":"select-lenvatinib","kind":"trial","name":"SELECT","route":"/trials/select-lenvatinib/"}],"pairing":[{"id":"targeted-before-io-nsclc","kind":"pairing","name":"Sequence: targeted therapy before immunotherapy in driver-positive NSCLC","route":"/pairings/targeted-before-io-nsclc/"}],"paper":[{"id":"paper-aggarwal-plasma-genotyping-personalised-therapy-jama-oncol-2019","kind":"paper","name":"Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer","route":"/key-papers/paper-aggarwal-plasma-genotyping-personalised-therapy-jama-oncol-2019/"},{"id":"paper-philip-kras-wild-type-pancreatic-ccr-2022","kind":"paper","name":"Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma","route":"/key-papers/paper-philip-kras-wild-type-pancreatic-ccr-2022/"},{"id":"paper-leighl-nile-cfdna-tissue-genotyping-ccr-2019","kind":"paper","name":"NILE: clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer","route":"/key-papers/paper-leighl-nile-cfdna-tissue-genotyping-ccr-2019/"},{"id":"paper-jordan-prospective-lung-adenocarcinoma-msk-cancer-discov-2017","kind":"paper","name":"Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies","route":"/key-papers/paper-jordan-prospective-lung-adenocarcinoma-msk-cancer-discov-2017/"},{"id":"paper-lindeman-lung-molecular-testing-guideline-jto-2018","kind":"paper","name":"Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors","route":"/key-papers/paper-lindeman-lung-molecular-testing-guideline-jto-2018/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"thyroid-cancer-markers","kind":"technology","name":"Thyroglobulin, calcitonin and CEA in thyroid cancer follow-up","route":"/technologies/thyroid-cancer-markers/"}],"person":[{"id":"alexander-drilon","kind":"person","name":"Alexander Drilon","route":"/people/alexander-drilon/"},{"id":"justin-gainor","kind":"person","name":"Justin F. Gainor","route":"/people/justin-gainor/"},{"id":"goto-koichi","kind":"person","name":"Koichi Goto","route":"/people/goto-koichi/"},{"id":"lori-wirth","kind":"person","name":"Lori J. Wirth","route":"/people/lori-wirth/"},{"id":"kohno-takashi","kind":"person","name":"Takashi Kohno","route":"/people/kohno-takashi/"}],"bottleneck":[{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"}],"idea":[{"id":"idea-tr1-tumour-agnostic-approval-standard","kind":"idea","name":"A standard for tumour-agnostic approvals: minimum histologies and hierarchical modelling","route":"/ideas/idea-tr1-tumour-agnostic-approval-standard/"},{"id":"idea-reg-tumour-agnostic-reliance","kind":"idea","name":"Adopt tumour-agnostic cancer drug labels across regions by reliance, not re-review","route":"/ideas/idea-reg-tumour-agnostic-reliance/"},{"id":"idea-moon-reciprocal-tumour-agnostic-approvals","kind":"idea","name":"Reciprocal recognition of tumour-agnostic and rare-indication approvals across regulators","route":"/ideas/idea-moon-reciprocal-tumour-agnostic-approvals/"}],"institution":[{"id":"kyushu-university-hospital","kind":"institution","name":"Kyushu University Hospital","route":"/institutions/kyushu-university-hospital/"},{"id":"ncc-hospital-east","kind":"institution","name":"National Cancer Center Hospital East","route":"/institutions/ncc-hospital-east/"},{"id":"nngm","kind":"institution","name":"nationales Netzwerk Genomische Medizin Lungenkrebs","route":"/institutions/nngm/"},{"id":"shanghai-chest-hospital","kind":"institution","name":"Shanghai Chest Hospital","route":"/institutions/shanghai-chest-hospital/"}],"roadmap":[{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}