CCT251545 enhances drug delivery and potentiates chemotherapy in multidrug-resistant cancers by Rac1-mediated macropinocytosis

Qin，Siyuan1; Zhang，Zhe1; Huang，Zhao1; Luo，Yinheng1; Weng，Ningna2; Li，Bowen1; Tang，Yongquan3; Zhou，Li1; Jiang，Jingwen1; Lu，Yi4,5; Shao，Jichun6; Xie，Na1; Nice，Edouard C.7; Chen，Zhe Sheng8,9; Zhang，Jian4,5; Huang，Canhua1

2023

10.1016/j.drup.2022.100906

Drug Resistance Updates   Impact Factor & Quartile

1368-7646

1532-2084

It was well known that P-glycoprotein (P-gp/ABCB1) is a master regulator of multidrug resistance (MDR) in cancers. However, the clinical benefit from blocking this pathway remains inconclusive, which motivates a paradigm shift towards alternative strategies for enhancing drug influx. Using a patient-derived organoid (PDO)-based drug screening platform, we report that the combined use of chemotherapy and CCT251545 (CCT) displays robust synergistic effect against PDOs and reduces proliferation of MDR cancer cells in vitro, and results in regression of xenograft tumors, reductions in metastatic dissemination and recurrence rate in vivo. The synergistic activity mediated by CCT can be mainly attributed to the intense uptake of chemotherapeutic agents into the cells, accompanied by alterations in cell phenotypes defined as a mesenchymal epithelial transformation (MET). Mechanistically, analysis of the transcriptome coupled with validation in cellular and animal models demonstrate that the chemosensitizing effect of CCT is profoundly affected by Rac1-dependent macropinocytosis. Furthermore, CCT binds to NAMPT directly, resulting in elevated NAD levels within MDR cancer cells. This effect promotes the assembly of adherents junction (AJ) components with cytoskeleton, which is required for continuous induction of macropinocytosis and consequent drug internalization. Overall, our results illustrate the potential use of CCT as a combination partner for the commonly used chemotherapeutic drugs in the management of MDR cancers.

CCT251545 Chemosensitization Drug resistance Macropinocytosis MDR cancers NAMPT

SCI

English

Corresponding

Basic and Applied Basic Research Foundation of Guangdong Province[2019B030302012];National Natural Science Foundation of China[81821002, 82130082, 81790251, 81972766];National Natural Science Foundation of China[81972420];National Natural Science Foundation of China[82173336];

WOS:000911492000001

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85144570052

Scopus

1.State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University,Collaborative Innovation Center for Biotherapy,Chengdu,610041,China
2.Department of Abdominal Oncology,West China Hospital of Sichuan University,Chengdu,Sichuan,610041,China
3.Department of Pediatric Surgery,West China Hospital,Sichuan University,Chengdu,China
4.School of Medicine,Southern University of Science and Technology Shenzhen,Guangdong,518055,China
5.Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen,Guangdong,China
6.Department of Urology,Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital),Chengdu,Sichuan,China
7.Department of Biochemistry and Molecular Biology,Monash University,Clayton,Australia
8.Department of Pharmaceutical Sciences,College of Pharmacy and Health Sciences,St. John's University,Queens,11439,United States
9.Institute for Biotechnology,St. John's University,Queens,11439,United States

Qin，Siyuan,Zhang，Zhe,Huang，Zhao,et al. CCT251545 enhances drug delivery and potentiates chemotherapy in multidrug-resistant cancers by Rac1-mediated macropinocytosis[J]. Drug Resistance Updates,2023,66.

Qin，Siyuan.,Zhang，Zhe.,Huang，Zhao.,Luo，Yinheng.,Weng，Ningna.,...&Huang，Canhua.(2023).CCT251545 enhances drug delivery and potentiates chemotherapy in multidrug-resistant cancers by Rac1-mediated macropinocytosis.Drug Resistance Updates,66.

Qin，Siyuan,et al."CCT251545 enhances drug delivery and potentiates chemotherapy in multidrug-resistant cancers by Rac1-mediated macropinocytosis".Drug Resistance Updates 66(2023).