RRC ID 71843
Author Sheng J, Kohno S, Okada N, Okahashi N, Teranishi K, Matsuda F, Shimizu H, Linn P, Nagatani N, Yamamura M, Harada K, Horike SI, Inoue H, Yano S, Kumar S, Kitajima S, Ajioka I, Takahashi C.
Title Treatment of Retinoblastoma 1-Intact Hepatocellular Carcinoma With Cyclin-Dependent Kinase 4/6 Inhibitor Combination Therapy.
Journal Hepatology
Abstract 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.
Volume 74(4)
Pages 1971-1993
Published 2021-10-1
DOI 10.1002/hep.31872
PMID 33931882
MeSH Aminopyridines / pharmacology Aminopyridines / therapeutic use Animals Benzimidazoles / pharmacology Benzimidazoles / therapeutic use Carcinoma, Hepatocellular / drug therapy* Carcinoma, Hepatocellular / genetics Cell Proliferation / drug effects* Cell Proliferation / genetics Cell Survival / drug effects Cyclin-Dependent Kinase 4 / antagonists & inhibitors Cyclin-Dependent Kinase 6 / antagonists & inhibitors Hep G2 Cells Humans In Vitro Techniques Liver Neoplasms / drug therapy* Liver Neoplasms / genetics Liver Neoplasms, Experimental / drug therapy Liver Neoplasms, Experimental / genetics Mice Neoplasm Transplantation Piperazines / pharmacology* Piperazines / therapeutic use Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use Purines / pharmacology Purines / therapeutic use Pyridines / pharmacology* Pyridines / therapeutic use Retinoblastoma Protein Tumor Suppressor Protein p53 / genetics Xenopus Proteins
IF 14.679
Human and Animal Cells 293T(RCB2202)