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Targeting UHRF1-dependent DNA repair selectively sensitizes KRAS mutant lung cancer to chemotherapy

Danmei Tian1, Jinshan Tang1, Xinran Geng2

  • 1Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, People's Republic of China.

Cancer Letters
|August 20, 2020
PubMed

Insights

Cardiac glycosides enhance chemotherapy for KRAS mutant lung cancer by inhibiting DNA repair. These compounds suppress UHRF1 expression, a key factor in DNA double-strand break repair, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • KRAS-mutant lung cancer is difficult to treat, with chemotherapy as the current standard.
  • Understanding chemotherapy sensitivity mechanisms in KRAS-mutant lung cancer is crucial for developing novel therapies.

Purpose of the Study:

  • To identify compounds that selectively enhance chemotherapy efficacy in KRAS-mutant lung cancer.
  • To elucidate the molecular mechanisms by which these compounds exert their effects.

Main Methods:

  • Compound library screening to identify potential therapeutic agents.
  • Quantitative mass spectrometry to analyze molecular targets.
  • In vitro and in vivo experiments to assess drug efficacy and mechanisms.

Main Results:

  • Cardiac glycosides were identified as agents that enhance chemotherapy effects on KRAS-mutant lung cancer.
  • Cardiac glycosides inhibit DNA double-strand break (DSB) repair by suppressing UHRF1 expression.
  • This inhibition is mediated by the suppression of the KRAS pathway, and UHRF1 manipulation affects drug sensitivity.

Conclusions:

  • Cardiac glycosides represent a promising therapeutic strategy for KRAS-mutant lung cancer.
  • Targeting UHRF1-mediated DNA repair offers a novel approach to overcome chemotherapy resistance.
  • The KRAS pathway is critical in mediating the effects of cardiac glycosides on DSB repair.
Keywords:
Cardiac glycosideChemo sensitizerChemotherapyCompound library screenDNA damage ResponseDNA repairDSB repairKRAS mutationUHRF1

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