Treatment of Retinoblastoma 1–Intact Hepatocellular Carcinoma With Cyclin‐Dependent Kinase 4/6 Inhibitor Combination Therapy

• Published in: Hepatology (Baltimore, Md.) Vol. 74; no. 4; pp. 1971 - 1993
• Main Authors: Sheng, Jindan, Kohno, Susumu, Okada, Nobuhiro, Okahashi, Nobuyuki, Teranishi, Kana, Matsuda, Fumio, Shimizu, Hiroshi, Linn, Paing, Nagatani, Naoko, Yamamura, Minako, Harada, Kenichi, Horike, Shin‐ichi, Inoue, Hiroshi, Yano, Seiji, Kumar, Sharad, Kitajima, Shunsuke, Ajioka, Itsuki, Takahashi, Chiaki
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.10.2021
• Subjects: AKT protein; Aminopyridines - pharmacology; Aminopyridines - therapeutic use; Animals; Antitumor activity; Apoptosis; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Breast cancer; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Cell cycle; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cell Survival - drug effects; Clinical trials; Combination therapy; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Enzyme inhibitors; Hep G2 Cells; Hepatocellular carcinoma; Hepatocytes; Hepatology; Humans; IKK protein; Immunogenicity; In Vitro Techniques; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - genetics; Malignancy; Mice; Neoplasm Transplantation; Phosphorylation; Piperazines - pharmacology; Piperazines - therapeutic use; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Purines - pharmacology; Purines - therapeutic use; Pyridines - pharmacology; Pyridines - therapeutic use; Retina; Retinoblastoma; Retinoblastoma Protein; Sarcoma; Senescence; Solid tumors; Tumor cell lines; Tumor Suppressor Protein p53 - genetics; Tumors; Xenopus Proteins
• DOI: 10.1002/hep.31872
• ISSN: 0270-9139

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.