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Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>CDK4\/6 inhibitors (CDK4\/6i) have been established as standard treatment against advanced Estrogen Receptor-positive breast cancers. These drugs are being tested against several cancers, including in combinations with other therapies. We identified the T172-phosphorylation of CDK4 as the step determining its activity, retinoblastoma protein (RB) inactivation, cell cycle commitment and sensitivity to CDK4\/6i. Poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinomas, the latter considered one of the most lethal human malignancies, represent major clinical challenges. Several molecular evidence suggest that CDK4\/6i could be considered for treating these advanced thyroid cancers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed by two-dimensional gel electrophoresis the CDK4 modification profile and the presence of T172-phosphorylated CDK4 in a collection of 98 fresh-frozen tissues and in 21 cell lines. A sub-cohort of samples was characterized by RNA sequencing and immunohistochemistry. Sensitivity to CDK4\/6i (palbociclib and abemaciclib) was assessed by BrdU incorporation\/viability assays. Treatment of cell lines with CDK4\/6i and combination with BRAF\/MEK inhibitors (dabrafenib\/trametinib) was comprehensively evaluated by western blot, characterization of immunoprecipitated CDK4 and CDK2 complexes and clonogenic assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CDK4 phosphorylation was detected in all well-differentiated thyroid carcinomas (n=29), 19\/20 PDTC, 16\/23 ATC and 18\/21 thyroid cancer cell lines, including 11 ATC-derived ones. Tumors and cell lines without phosphorylated CDK4 presented very high p16\n                      <jats:italic>\n                        <jats:sup>CDKN2A<\/jats:sup>\n                      <\/jats:italic>\n                      levels, which were associated with proliferative activity. Absence of CDK4 phosphorylation in cell lines was associated with CDK4\/6i insensitivity.\n                      <jats:italic>RB1<\/jats:italic>\n                      defects (the primary cause of intrinsic CDK4\/6i resistance) were not found in 5\/7 tumors without detectable phosphorylated CDK4. A previously developed 11-gene expression signature identified the likely unresponsive tumors, lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib\/trametinib by completely and permanently arresting proliferation. These combinations prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study supports further clinical evaluation of CDK4\/6i and their combination with anti-BRAF\/MEK therapies as a novel effective treatment against advanced thyroid tumors. Moreover, the complementary use of our 11 genes predictor with p16\/KI67 evaluation could represent a prompt tool for recognizing the intrinsically CDK4\/6i insensitive patients, who are potentially better candidates to immediate chemotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2023.1247542","type":"journal-article","created":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T22:59:22Z","timestamp":1698361162000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["CDK4 phosphorylation status and rational use for combining CDK4\/6 and BRAF\/MEK inhibition in advanced thyroid carcinomas"],"prefix":"10.3389","volume":"14","author":[{"given":"Jaime 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