Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints Academic Article uri icon

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abstract

  • In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a pre-existing synthetic lethal combination. We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy. Delivery of siRNA-peptide nanoplexes co-targeting MK2 and XPA to pre-existing p53-deficient tumors in a highly aggressive, immunocompetent mouse model of lung adenocarcinoma improves long-term survival and cisplatin response beyond those of the synthetic lethal p53 mutant/MK2 combination alone. These findings establish a mechanism for co-targeting DNA damage-induced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment.

authors

  • Kong, Yi Wen
  • Dreaden, Erik C
  • Morandell, Sandra
  • Zhou, Wen
  • Dhara, Sanjeev S
  • Sriram, Ganapathy
  • Lam, Fred
  • Patterson, Jesse C
  • Quadir, Mohiuddin
  • Dinh, Anh
  • Shopsowitz, Kevin E
  • Varmeh, Shohreh
  • Yilmaz, Ömer H
  • Lippard, Stephen J
  • Reinhardt, H Christian
  • Hemann, Michael T
  • Hammond, Paula T
  • Yaffe, Michael B

publication date

  • December 2020