Exploiting replication stress for synthetic lethality in MYC-driven cancers.

The oncoprotein MYC, overexpressed in more than 70% of human cancers, plays a pivotal role in regulating gene transcription and has long been recognized as a promising target for cancer therapy. However, no MYC-targeted drug has been approved for clinical use, largely due to the lack of a well-defined druggable domain and its nuclear localization. MYC-overexpressing cancer cells exhibit increased replication stress, driven by factors such as elevated replication origin firing, nucleotide depletion, replication-transcription conflicts, and heightened reactive oxygen species (ROS) production. Simultaneously, MYC activates compensatory mechanisms, including enhanced DNA repair, checkpoint-mediated cell cycle regulation, and metabolic reprogramming, to mitigate this stress and support cell survival. Interfering with these compensatory pathways exacerbates replication stress, leading to synthetic lethality in MYC-driven cancer cells. In this review, we summarize recent advances in leveraging replication stress to achieve synthetic lethality in MYC-driven cancers. Furthermore, we discuss current strategies targeting replication stress, highlighting new opportunities for the development of therapies against MYC-driven malignancies.