{"entity":{"id":"thyroid-cancer-signalling","kind":"pathway","name":"Thyroid cancer (KEGG map)","aka":["KEGG hsa05216","Thyroid cancer"],"tldr":"This KEGG map shows thyroid cancers driven by one relay, the MAPK pathway: RET or NTRK fusions and BRAF mutations in papillary tumours, RAS mutations or PAX8-PPARG fusion in follicular tumours, and TP53 loss marking anaplastic cancer. It matters because RET, NTRK and BRAF alterations each have their own drug, and MAPK blockade can restore iodine uptake.","summary":"Thyroid cancer is the most common endocrine malignancy and more than 95 percent of cases arise from follicular cells. KEGG map hsa05216 draws the spectrum from indolent well-differentiated papillary (PTC) and follicular (FTC) carcinoma to aggressive undifferentiated (anaplastic) carcinoma. Somatic RET and TRK (NTRK) rearrangements are found almost exclusively in PTC and appear early; BRAF V600E is the other dominant PTC driver, and all three feed RAS-RAF-MEK-ERK. FTC is marked by aneuploidy, RAS (KRAS, NRAS) mutations and PAX8-PPARG fusions, which alter PPAR-gamma-mediated transcription. Reduced E-cadherin releases beta-catenin signalling, and TP53 inactivation is crucial in dedifferentiation to anaplastic carcinoma.\n\nCabanillas, McFadden and Durante, The Lancet, 2016 (doi:10.1016/S0140-6736(16)30172-6) review the disease: mutually exclusive MAPK drivers (BRAF, RAS, RET/PTC, NTRK) define most differentiated thyroid cancers, MAPK activation lowers expression of the sodium-iodide symporter and so causes radioiodine resistance, and RET point mutations drive medullary thyroid cancer.\n\nWhat drugs do about it: radioactive iodine treats differentiated tumours that still take up iodine; the multikinase inhibitors lenvatinib and sorafenib (both listed by KEGG) treat radioiodine-refractory disease; selpercatinib and pralsetinib treat RET-altered tumours including medullary cancer, replacing vandetanib and cabozantinib for most patients; larotrectinib, entrectinib and repotrectinib treat NTRK fusion tumours; dabrafenib plus trametinib is approved for BRAF V600E anaplastic thyroid cancer; and MAPK inhibition (selumetinib, dabrafenib) can restore iodine uptake in refractory tumours, a strategy called redifferentiation.","asOf":"2026-09-10","links":[{"label":"KEGG map hsa05216","url":"https://www.kegg.jp/pathway/hsa05216"},{"label":"Review: Thyroid cancer (Lancet seminar)","url":"https://doi.org/10.1016/S0140-6736(16)30172-6"}],"tags":[],"related":["ras-mapk","rtk-activation"],"cancers":["thyroid"],"sections":[],"technologies":[],"targets":["ret","ntrk","kras","braf","mek","tp53"],"drugs":["selpercatinib","pralsetinib","vandetanib","cabozantinib","larotrectinib","entrectinib","repotrectinib","dabrafenib","trametinib","lenvatinib","sorafenib","selumetinib","radioactive-iodine"],"companies":[],"institutions":[],"pathways":["ras-mapk","rtk-activation","p53-cell-cycle","wnt","emt"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-cabanillas-lancet"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A thermostat where the heating relay (MAPK) is stuck on. Different faults jam it: a mis-wired fuse (RET or NTRK fusion), a broken switch (BRAF), or a stuck sensor (RAS). Because it is the same relay each time, an engineer can usually find the exact broken part and swap it, and fixing it even lets the room's iodine meter work again.","nodes":[{"id":"ret","label":"RET fusion / mutation","x":12,"y":6,"targetId":"ret"},{"id":"ntrk","label":"NTRK fusion","x":38,"y":6,"targetId":"ntrk"},{"id":"ras","label":"KRAS / NRAS (follicular)","x":62,"y":6,"targetId":"kras"},{"id":"pax8","label":"PAX8-PPARG fusion","x":88,"y":6},{"id":"braf","label":"BRAF V600E (papillary)","x":38,"y":30,"targetId":"braf"},{"id":"mek","label":"MEK / ERK","x":38,"y":52,"targetId":"mek"},{"id":"nis","label":"Sodium-iodide symporter (NIS)","x":10,"y":72},{"id":"cdh1","label":"E-cadherin / beta-catenin","x":70,"y":52},{"id":"p53","label":"TP53 (dedifferentiation)","x":88,"y":72,"targetId":"tp53"},{"id":"out","label":"Papillary / follicular to anaplastic","x":50,"y":94}],"edges":[{"from":"ret","to":"braf","type":"activates"},{"from":"ntrk","to":"braf","type":"activates"},{"from":"ras","to":"braf","type":"activates"},{"from":"braf","to":"mek","type":"activates"},{"from":"mek","to":"out","type":"activates"},{"from":"mek","to":"nis","type":"inhibits"},{"from":"pax8","to":"out","type":"activates"},{"from":"cdh1","to":"out","type":"activates"},{"from":"p53","to":"out","type":"inhibits"}],"interventions":["RET-altered tumours (including medullary cancer): selpercatinib, pralsetinib; older options vandetanib, cabozantinib","NTRK fusion tumours: larotrectinib, entrectinib, repotrectinib","BRAF V600E anaplastic thyroid cancer: dabrafenib plus trametinib","Radioiodine-refractory differentiated cancer: lenvatinib, sorafenib (listed by KEGG)","Redifferentiation: MAPK inhibition (selumetinib, dabrafenib) to restore iodine uptake before radioactive iodine","Differentiated cancer that still takes up iodine: radioactive iodine after surgery"]},"route":"/pathways/thyroid-cancer-signalling/","neighbours":{"pathway":[{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"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":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"cancer":[{"id":"thyroid","kind":"cancer","name":"Thyroid cancer","route":"/cancers/thyroid/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"mek","kind":"target","name":"MEK1/2","route":"/targets/mek/"},{"id":"ntrk","kind":"target","name":"NTRK","route":"/targets/ntrk/"},{"id":"ret","kind":"target","name":"RET","route":"/targets/ret/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"entrectinib","kind":"drug","name":"Entrectinib","route":"/drugs/entrectinib/"},{"id":"larotrectinib","kind":"drug","name":"Larotrectinib","route":"/drugs/larotrectinib/"},{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"},{"id":"pralsetinib","kind":"drug","name":"Pralsetinib","route":"/drugs/pralsetinib/"},{"id":"radioactive-iodine","kind":"drug","name":"Radioactive iodine (I-131)","route":"/drugs/radioactive-iodine/"},{"id":"repotrectinib","kind":"drug","name":"Repotrectinib","route":"/drugs/repotrectinib/"},{"id":"selpercatinib","kind":"drug","name":"Selpercatinib","route":"/drugs/selpercatinib/"},{"id":"selumetinib","kind":"drug","name":"Selumetinib","route":"/drugs/selumetinib/"},{"id":"sorafenib","kind":"drug","name":"Sorafenib","route":"/drugs/sorafenib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"},{"id":"vandetanib","kind":"drug","name":"Vandetanib","route":"/drugs/vandetanib/"}],"paper":[{"id":"paper-cabanillas-lancet","kind":"paper","name":"Thyroid cancer","route":"/key-papers/paper-cabanillas-lancet/"}]}}