AZD5153 reverses palbociclib resistance in ovarian cancer by inhibiting cell cycle-related proteins and the MAPK/PI3K-AKT pathway.

Abstract

The CDK4/6 inhibitor, palbociclib has recently entered clinic-trial stage for breast cancer treatment. However, translating its efficacy to other solid tumors has been challenging, especially for aggressive solid tumors. We found that the effect of palbociclib as a single agent was limited due to primary and acquired resistance in multiple ovarian cancer (OC) models. Among these, patient-derived organoid and xenograft models are two most representative models of drug responsiveness in patients with OC. In preclinical models, this study demonstrated that activated MAPK/PI3K-AKT pathway and cell cycle-related proteins induced the resistance to palbociclib, which was overcome by the addition of the bromodomain protein 4 (BRD4) inhibitor AZD5153. Moreover, this study revealed that AZD5153 and palbociclib had a synergistic lethal effect on inducing the cell cycle arrest and increasing apoptosis, even in RB-deficient cell lines. Based on these results, it is anticipated that this class of drugs, including AZD5153, which inhibit the cell cycle-related protein and MAPK/PI3K-AKT pathway, will exhibit synergistic effects with palbociclib in OC.

• Authors: Chen Liu, Yuhan Huang, Tianyu Qin, Lixin You, Funian Lu, Dianxing Hu, Rourou Xiao, Xu Qin, Ensong Guo, Bin Yang, Xi Li, Junpeng Fan, Xiong Li, Yu Fu, Si Liu, Zhuozi Wang, Yingyu Dou, Wei Wang, Wenting Li, Xiaohang Yang, Jingbo Liu, Wenju Peng, Li Zhang, Yaoyuan Cui, Chaoyang Sun, Gang Chen
• Journal: Cancer letters (Cancer Lett) Vol. 528 Pg. 31-44 (03 01 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 34942306 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier B.V.

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• Heterocyclic Compounds, 2-Ring
• Piperazines
• Pyrazoles
• Pyridazines
• Pyridines
• AZD5153
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase Kinases
• palbociclib

Topics

• Animals
• Antineoplastic Agents
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Cycle Proteins (drug effects)
• Cell Line, Tumor
• Female
• Heterocyclic Compounds, 2-Ring (pharmacology, therapeutic use)
• Humans
• Mice
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Ovarian Neoplasms (drug therapy)
• Phosphatidylinositol 3-Kinases (metabolism)
• Piperazines (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrazoles (pharmacology, therapeutic use)
• Pyridazines (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays