MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription

EBioMedicine. 2019 Oct;48:289-300. doi: 10.1016/j.ebiom.2019.10.003. Epub 2019 Oct 21.

Abstract

Background: Thymidylate synthase (TYMS) is a successful chemotherapeutic target for anticancer therapy. Numerous TYMS inhibitors have been developed and used for treating gastrointestinal cancer now, but they have limited clinical benefits due to the prevalent unresponsiveness and toxicity. It is urgent to identify a predictive biomarker to guide the precise clinical use of TYMS inhibitors.

Methods: Genome-scale CRISPR-Cas9 knockout screening was performed to identify potential therapeutic targets for treating gastrointestinal tumours as well as key regulators of raltitrexed (RTX) sensitivity. Cell-based functional assays were used to investigate how MYC regulates TYMS transcription. Cancer patient data were used to verify the correlation between drug response and MYC and/or TYMS mRNA levels. Finally, the role of NIPBL inactivation in gastrointestinal cancer was evaluated in vitro and in vivo.

Findings: TYMS is essential for maintaining the viability of gastrointestinal cancer cells, and is selectively inhibited by RTX. Mechanistically, MYC presets gastrointestinal cancer sensitivity to RTX through upregulating TYMS transcription, supported by TCGA data showing that complete response cases to TYMS inhibitors had significantly higher MYC and TYMS mRNA levels than those of progressive diseases. NIPBL inactivation decreases the therapeutic responses of gastrointestinal cancer to RTX through blocking MYC.

Interpretation: Our study unveils a mechanism of how TYMS is transcriptionally regulated by MYC, and provides rationales for the precise use of TYMS inhibitors in the clinic.

Funding: This work was financially supported by grants of NKRDP (2016YFC1302400), STCSM (16JC1406200), NSFC (81872890, 81322034, 81372346) and CAS (QYZDB-SSW-SMC034, XDA12020210).

Keywords: Genome-scale CRISPR-Cas9 knockout screening; MYC; NIPBL; Raltitrexed; Thymidylate synthase.

MeSH terms

  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Resistance / genetics*
  • Folic Acid Antagonists / pharmacology*
  • Gastrointestinal Neoplasms / genetics*
  • Gastrointestinal Neoplasms / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Genes, myc*
  • Humans
  • Thymidylate Synthase / antagonists & inhibitors
  • Thymidylate Synthase / genetics*
  • Thymidylate Synthase / metabolism
  • Transcription, Genetic

Substances

  • Folic Acid Antagonists
  • TYMS protein, human
  • Thymidylate Synthase