Chemogenetic screen identifies EphA2 as a synthetic lethal vulnerability in MYC-driven triple-negative breast cancer.

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.