Jindan Sheng1, Susumu Kohno1, Nobuhiro Okada2, Nobuyuki Okahashi3, Kana Teranishi1, Fumio Matsuda3, Hiroshi Shimizu3, Paing Linn1, Naoko Nagatani1, Minako Yamamura4, Kenichi Harada4, Shin-Ichi Horike5, Hiroshi Inoue6, Seiji Yano1, Sharad Kumar7, Shunsuke Kitajima1,8,9, Itsuki Ajioka10,11, Chiaki Takahashi1. 1. Cancer Research Institute, Kanazawa University, Kanazawa, Japan. 2. Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan. 3. Graduate School of Information Science and Technology, Osaka University, Suita, Japan. 4. Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan. 5. Advanced Science Research Center, Kanazawa University, Kanazawa, Japan. 6. Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Japan. 7. Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia. 8. Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. 9. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. 10. Center for Brain Integration Research, Tokyo Medical Dental University, Tokyo, Japan. 11. Kanagawa Institute of Industrial Science and Technology, Kanagawa, Japan.
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.
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.
Authors: Mazen A Juratli; He Zhou; Elsie Oppermann; Wolf O Bechstein; Andreas Pascher; Felix K-H Chun; Eva Juengel; Jochen Rutz; Roman A Blaheta Journal: Cancers (Basel) Date: 2022-05-14 Impact factor: 6.575