{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:17:07Z","timestamp":1791919027693,"version":"4.3.4"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T00:00:00Z","timestamp":1733875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The insulin-like growth factor 1 receptor (IGF-1R) and the thyrotropin receptor (TSH-R) are expressed on orbital cells and thyrocytes. These receptors are targeted in autoimmune-induced thyroid eye disease (TED). Effective therapeutic treatment of TED inhibits activation of the IGF-1R\/TSH-R complex.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The inhibitory effect on cell proliferation of a small molecule targeting IGF-1R phosphorylation (Linsitinib) was investigated in an IGF-1R expressing cell line and a Chinese Hamster Ovary (CHO) cell line overexpressing TSH-R. An IGF-1R monoclonal antibody antagonist, Teprotumumab served as control. Both cell lines were plated in a 96-well format and treated with both compounds for 24 hours. After addition of tetrazolium, absorbance was measured. The apoptosis marker caspase-3\/7 activity was measured. The half-maximal inhibitory concentration (IC\n                      <jats:sub>50<\/jats:sub>\n                      ) of TSH-R-Ab induced stimulation (stimulatory monoclonal antibody, mAb, M22) of the TSH-R cell line was evaluated with a cell-based bioassay for blocking TSH-R-Ab. Cells were treated with ten rising concentrations of either Linsitinib, Linsitinib + Metformin, Teprotumumab, or a blocking TSH-R mAb (K1-70).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Linsitinib strongly inhibited the proliferation of both cell lines at several concentrations: 31,612.5 ng\/mL (IGF-1R cell line -78%, P=0.0031, TSH-R cell line -75%, P=0.0059), and at 63,225 ng\/mL (IGF-1R cell line -73%, P=0.0073, TSH-R cell line -73%, P=0.0108). Linsitinib induced apoptosis of both cell lines, both morphologically confirmed and with an increased caspase-3\/7 activity at concentrations of 31,612.5 ng\/mL (IGF-1R cell line P=0.0158, TSH-R cell line P=0.0048) and 63,225 ng\/mL (IGF-1R cell line P=0.0005, TSH-R cell line P=0.0020). Linsitinib markedly inhibited proliferation of the IGF-1R cell line at all concentrations compared to Teprotumumab (P=0.0286). Teprotumumab inhibition was significant only at 15,806.25 ng\/mL with the TSH-R cell line (-15%, P=0.0396). In addition, in the TSH-R-Ab blocking bioassay, Linsitinib and the tested compounds demonstrated strong inhibition across all ten dilutions (100%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Linsitinib effectively induces apoptosis and inhibits proliferation of both IGF-1R and TSH-R expressing target cells, therefore demonstrating its therapeutic potential to block the reported crosstalk of the two mediators in autoimmune TED.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2024.1488220","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T02:06:04Z","timestamp":1733882764000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Linsitinib inhibits proliferation and induces apoptosis of both IGF-1R and TSH-R expressing 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