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We evaluated the impact of CDK4\/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient\u2010derived ones, using various approaches including RNA\u2010sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4\/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172\u2010phosphorylated CDK4. This was associated with high p16\n                    <jats:sup>INK4A<\/jats:sup>\n                    (\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    ) levels that accompany\n                    <jats:italic>RB1<\/jats:italic>\n                    defects or inactivation, or (unexpectedly)\n                    <jats:italic>CCNE1<\/jats:italic>\n                    overexpression in the presence of wild\u2010type\n                    <jats:italic>RB1<\/jats:italic>\n                    . Prolonged palbociclib treatment irreversibly inhibited proliferation despite re\u2010induction of cell cycle genes upon drug washout. A senescence\u2010associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4\/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    ) expression, which was also observed in public datasets in tumours from short\u2010survival patients. Our study supports the evaluation of CDK4\/6 inhibitors for MPM treatment, in monotherapy or combination therapy.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13351","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T07:37:57Z","timestamp":1669880277000},"page":"866-894","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Preclinical evaluation of\n                    <scp>CDK4<\/scp>\n                    phosphorylation predicts high sensitivity of pleural mesotheliomas to\n                    <scp>CDK4<\/scp>\n                    \/6 inhibition"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3028-8223","authenticated-orcid":false,"given":"Sabine","family":"Paternot","sequence":"first","affiliation":[{"name":"Institut de Recherche Interdisciplinaire en Biologie Humaine et Mol\u00e9culaire (IRIBHM) Universit\u00e9 Libre de Bruxelles  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