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Chemogenetic screen identifies EphA2 as a synthetic lethal vulnerability in MYC-driven triple-negative breast cancer
Meng Ye1, Zixin Wang2, Yuxin Wang2
1School of Pharmacy, Guangdong Pharmaceutical University, Guangdong, China; State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Abstract:
The MYC oncoprotein is a key driver of various cancers and is particularly relevant in triple-negative breast cancer (TNBC), where its dysregulated activation promotes aggressive tumor growth, metastasis, and resistance to treatment. Despite its central role in cancer development, directly targeting MYC proves challenging due to its disordered structure and lack of druggable pockets. Synthetic lethality, a strategy that exploits secondary vulnerabilities in MYC-driven cancer cells, offers a promising therapeutic approach. In this study, we establish a chemogenetic screening platform to identify compounds that selectively target MYC-driven cancer cells. We screen a library of approximately 600 kinase inhibitors and identify ALW-II-41-27, an EphA2 inhibitor, as a top hit. ALW-II-41-27 demonstrates strong MYC-selective cytotoxicity and induces apoptosis in MYC-activated cells through the intrinsic apoptotic pathway. Importantly, this apoptotic response is independent of p53 status, which is frequently inactivated by loss-of-function mutations in MYC-driven cancers. In vivo, ALW-II-41-27 effectively inhibits tumor growth in MDA-MB-231 and MDA-MB-468 TNBC xenografts without apparent toxicity. These findings highlight EPHA2 as a novel synthetic lethal partner of MYC and suggest that targeting EPHA2 could offer a promising therapeutic strategy for MYC-driven TNBC.
Insights
Researchers identified a new way to target MYC-driven cancers, like triple-negative breast cancer (TNBC). An EphA2 inhibitor, ALW-II-41-27, selectively kills cancer cells by triggering apoptosis, offering a potential new treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The MYC oncoprotein drives many cancers, including triple-negative breast cancer (TNBC), leading to aggressive tumor growth and treatment resistance.
- Directly targeting MYC is difficult due to its structure, making synthetic lethality a promising therapeutic strategy.
- Identifying vulnerabilities in MYC-driven cancer cells is crucial for developing new treatments.
Purpose of the Study:
- To establish a chemogenetic screening platform to identify compounds selectively targeting MYC-driven cancer cells.
- To discover novel synthetic lethal partners of MYC for therapeutic intervention in TNBC.
Main Methods:
- A chemogenetic screening platform was developed and utilized.
- Approximately 600 kinase inhibitors were screened to identify compounds with MYC-selective cytotoxicity.
- The efficacy and mechanism of action of the identified inhibitor (ALW-II-41-27) were evaluated in vitro and in vivo.
Main Results:
- ALW-II-41-27, an EphA2 inhibitor, was identified as a potent MYC-selective compound.
- ALW-II-41-27 induced apoptosis in MYC-activated cells via the intrinsic apoptotic pathway, irrespective of p53 status.
- In vivo studies showed ALW-II-41-27 effectively inhibited TNBC xenograft growth without apparent toxicity.
Conclusions:
- EphA2 is a novel synthetic lethal partner of MYC.
- Targeting EphA2 represents a promising therapeutic strategy for MYC-driven cancers, particularly TNBC.
- ALW-II-41-27 demonstrates potential as a novel therapeutic agent for TNBC.
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