PMID- 35814226
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 13
DP  - 2022
TI  - Gilteritinib Enhances Anti-Tumor Efficacy of CDK4/6 Inhibitor, Abemaciclib in 
      Lung Cancer Cells.
PG  - 829759
LID - 10.3389/fphar.2022.829759 [doi]
LID - 829759
AB  - Abemaciclib is a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor approved for the 
      treatment of metastatic breast cancer. Preclinical studies suggest that 
      abemaciclib has the potential for lung cancer treatment. However, several 
      clinical trials demonstrate that monotherapy with abemaciclib has no obvious 
      superiority than erlotinib to treat lung cancer patients, limiting its 
      therapeutic options for lung cancer treatment. Here, we show that the US Food and 
      Drug Administration (FDA)-approved drug, gilteritinib, enhances the cytotoxicity 
      of abemaciclib through inducing apoptosis and senescence in lung cancer cells. 
      Interestingly, abemaciclib in combination with gilteritinib leads to excessive 
      accumulation of vacuoles in lung cancer cells. Mechanistically, combined 
      abemaciclib and gilteritinib induces complete inactivation of AKT and 
      retinoblastoma (Rb) pathways in lung cancer cells. In addition, RNA-sequencing 
      data demonstrate that combination of abemaciclib and gilteritinib treatment 
      induces G2 phase cell-cycle arrest, inhibits DNA replication, and leads to 
      reduction in homologous recombination associated gene expressions. Of note, 
      abemaciclib-resistant lung cancer cells are more sensitive to gilteritinib 
      treatment. In a mouse xenograft model, combined abemaciclib and gilteritinib is 
      more effective than either drug alone in suppressing tumor growth and appears to 
      be well tolerated. Together, our findings support the combination of abemaciclib 
      with gilteritinib as an effective strategy for the treatment of lung cancer, 
      suggesting further evaluation of their efficacy is needed in a clinical trial.
CI  - Copyright (c) 2022 Sun, Talukder, Cao and Chen.
FAU - Sun, Chao-Yue
AU  - Sun CY
AD  - College of Biological and Pharmaceutical Engineering, West Anhui University, 
      Lu'an, China.
FAU - Talukder, Milton
AU  - Talukder M
AD  - Department of Physiology and Pharmacology, Faculty of Animal Science and 
      Veterinary Medicine, Patuakhali Science and Technology University, Barishal, 
      Bangladesh.
FAU - Cao, Di
AU  - Cao D
AD  - State Key Laboratory of Oncology in South China, Department of Radiology, Sun 
      Yat-Sen University Cancer Center, Key Laboratory of Nasopharyngeal Carcinoma 
      Diagnosis and Therapy, Guangzhou, China.
FAU - Chen, Cun-Wu
AU  - Chen CW
AD  - College of Biological and Pharmaceutical Engineering, West Anhui University, 
      Lu'an, China.
LA  - eng
PT  - Journal Article
DEP - 20220623
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC9262324
OTO - NOTNLM
OT  - Akt
OT  - CDK4/6
OT  - RB
OT  - abemaciclib
OT  - gilteritinib
OT  - lung cancer
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest. The reviewer DR declared a shared parent affiliation with 
      the author DC to the handling editor at the time of review
EDAT- 2022/07/12 06:00
MHDA- 2022/07/12 06:01
PMCR- 2022/06/23
CRDT- 2022/07/11 04:13
PHST- 2021/12/06 00:00 [received]
PHST- 2022/06/08 00:00 [accepted]
PHST- 2022/07/11 04:13 [entrez]
PHST- 2022/07/12 06:00 [pubmed]
PHST- 2022/07/12 06:01 [medline]
PHST- 2022/06/23 00:00 [pmc-release]
AID - 829759 [pii]
AID - 10.3389/fphar.2022.829759 [doi]
PST - epublish
SO  - Front Pharmacol. 2022 Jun 23;13:829759. doi: 10.3389/fphar.2022.829759. 
      eCollection 2022.