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Treatment of Retinoblastoma 1–Intact Hepatocellular Carcinoma With Cyclin‐Dependent Kinase 4/6 Inhibitor Combination Therapy
Author(s) -
Sheng Jindan,
Kohno Susumu,
Okada Nobuhiro,
Okahashi Nobuyuki,
Teranishi Kana,
Matsuda Fumio,
Shimizu Hiroshi,
Linn Paing,
Nagatani Naoko,
Yamamura Minako,
Harada Kenichi,
Horike Shinichi,
Inoue Hiroshi,
Yano Seiji,
Kumar Sharad,
Kitajima Shunsuke,
Ajioka Itsuki,
Takahashi Chiaki
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31872
Subject(s) - palbociclib , cancer research , medicine , cyclin dependent kinase 4 , retinoblastoma , cyclin dependent kinase , cancer , kinase , cell cycle , hepatoblastoma , hepatocellular carcinoma , retinoblastoma protein , biology , breast cancer , cyclin dependent kinase 2 , metastatic breast cancer , biochemistry , gene , microbiology and biotechnology
Background and Aims Synthetic cyclin‐dependent 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. Approach and Results Loss of all Rb family members in transformation related protein 53 ( Trp53 ) −/− mouse liver resulted in liver tumor reminiscent of human HCC, and re‐expression 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)β inhibitor Bay 11‐7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF‐κB activation. Combination therapy using palbociclib with Bay 11‐7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK–NF‐κB or AKT pathway enhanced effects of palbociclib on RB1‐intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. Conclusions In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1‐intact cancers including HCC when combined with an appropriate kinase inhibitor.