{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T16:20:33Z","timestamp":1780590033528,"version":"3.54.1"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Synthetic cyclin\u2010dependent kinase (CDK) 4\/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4\/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Loss of all <jats:italic toggle=\"yes\">Rb<\/jats:italic> family members in transformation related protein 53 (<jats:italic toggle=\"yes\">Trp53<\/jats:italic>)<jats:sup>\u2212\/\u2212<\/jats:sup> mouse liver resulted in liver tumor reminiscent of human HCC, and re\u2010expression of RB1 sensitized these tumors to a CDK4\/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)\u03b2 inhibitor Bay 11\u20107082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKK\u03b1\/\u03b2 phosphorylation and NF\u2010\u03baB activation. Combination therapy using palbociclib with Bay 11\u20107082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK\u2013NF\u2010\u03baB or AKT pathway enhanced effects of palbociclib on RB1\u2010intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In conclusion, CDK4\/6 inhibitors have a potential to treat a wide variety of RB1\u2010intact cancers including HCC when combined with an appropriate kinase inhibitor.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31872","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T02:02:55Z","timestamp":1619834575000},"page":"1971-1993","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":32,"title":["Treatment of Retinoblastoma 1\u2013Intact Hepatocellular Carcinoma With Cyclin\u2010Dependent Kinase 4\/6 Inhibitor Combination 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