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Exploiting replication stress for synthetic lethality in MYC-driven cancers

Yuan Zhang1,2, Meng Ye1,2, Xin Luan1,2

  • 1School of Pharmacy, Guangdong Pharmaceutical University Guangzhou 510006, Guangdong, China.

American Journal of Cancer Research
|May 15, 2025
PubMed

Insights

Targeting MYC-driven cancers involves exploiting their replication stress. Interfering with cancer cell survival mechanisms induces synthetic lethality, offering new therapeutic strategies for MYC-overexpressing malignancies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The oncoprotein MYC is overexpressed in over 70% of human cancers, regulating gene transcription.
  • MYC is a promising cancer therapy target, but lacks approved drugs due to its undefined druggable domain and nuclear localization.
  • MYC-overexpressing cancers face replication stress from increased origin firing, nucleotide depletion, replication-transcription conflicts, and reactive oxygen species (ROS).

Purpose of the Study:

  • To review recent advances in using replication stress for synthetic lethality in MYC-driven cancers.
  • To discuss current strategies targeting replication stress.
  • To highlight new therapeutic opportunities for MYC-driven malignancies.

Main Methods:

  • Review of current scientific literature on MYC, replication stress, and synthetic lethality.
  • Analysis of compensatory mechanisms in MYC-overexpressing cancer cells.
  • Discussion of therapeutic strategies targeting replication stress pathways.

Main Results:

  • MYC-overexpressing cancer cells exhibit significant replication stress.
  • MYC activates compensatory pathways (DNA repair, cell cycle checkpoints, metabolic reprogramming) to manage this stress.
  • Interfering with these compensatory pathways leads to synthetic lethality in MYC-driven cancer cells.

Conclusions:

  • Leveraging replication stress presents a promising synthetic lethality strategy for MYC-driven cancers.
  • Targeting compensatory pathways offers new avenues for developing MYC-targeted therapies.
  • Further research into replication stress mechanisms can guide the development of novel cancer treatments.
Keywords:
DNA replication stressMYCsynthetic lethality

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