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Updated: Apr 3, 2026
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
EphB4 inhibitor overcome the acquired resistance to cisplatin in melanomas xenograft model
Xiaokun Yang1, Yadong Yang2, Shuqian Tang2
1Department of Dermatology, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China; Department of Emergency, General Hospital of Chengdu Military Command Area, Chengdu 610083, Sichuan Province, PR China.
Abstract:
The purpose of this paper is to investigate the possible mechanisms of resistance to chemotherapy in melanoma from the perspective of molecular biology and to discuss the strategies to overcome them. Cisplatin, a DNA-damaging compound that triggers apoptotic cell death, is commonly used in the treatment of malignant melanoma. However, most patients develop mechanisms of acquired resistance and about 25% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. In the current study, we reported the tumor xenografts of the human A375 melanoma, after 40-weeks' consecutive therapy with cisplatin that developed resistance as a result of EphB4 overexpression. Moreover, the expression of phospho-AKT and phospho-ERK were significantly increased in cisplatin-resistant tumors. In addition, combined of cisplatin with EphB4 selective inhibitor could abrogate this acquired mechanism of drug resistance due to an enhanced apoptotic effect in cisplatin-resistant xenografts. In summary, these results help to understand the mechanisms of acquired resistance to chemotherapy and provide important information for clinical treatment strategies.
Insights
Melanoma chemotherapy resistance can be overcome by targeting EphB4 overexpression. Combining cisplatin with an EphB4 inhibitor enhances apoptosis and drug efficacy in resistant tumors.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- Malignant melanoma often develops resistance to chemotherapy, limiting treatment effectiveness.
- Cisplatin, a DNA-damaging agent, induces apoptosis but faces acquired and intrinsic resistance in melanoma patients.
- Understanding resistance mechanisms is crucial for improving melanoma treatment strategies.
Purpose of the Study:
- To investigate molecular mechanisms of chemotherapy resistance in melanoma.
- To identify strategies for overcoming cisplatin resistance in melanoma.
- To explore the role of EphB4 in acquired cisplatin resistance.
Main Methods:
- Utilized human A375 melanoma tumor xenografts for drug resistance studies.
- Administered 40-week consecutive cisplatin therapy to induce acquired resistance.
- Analyzed EphB4, phospho-AKT, and phospho-ERK expression in resistant tumors.
- Evaluated the efficacy of combined cisplatin and EphB4 selective inhibitor therapy.
Main Results:
- Cisplatin-resistant melanoma xenografts exhibited significant EphB4 overexpression.
- Increased expression of phospho-AKT and phospho-ERK was observed in resistant tumors.
- Combined cisplatin and EphB4 inhibitor therapy abrogated acquired resistance.
- Enhanced apoptotic effects were noted in resistant xenografts treated with the combination therapy.
Conclusions:
- EphB4 overexpression is a key mechanism of acquired cisplatin resistance in melanoma.
- Targeting EphB4 in combination with cisplatin can overcome drug resistance.
- These findings offer insights for developing improved clinical treatment strategies for melanoma.
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