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

• Main Authors: Kong, Yi Wen (Author), Dreaden, Erik C (Author), Morandell, Sandra (Author), Zhou, Wen (Author), Dhara, Sanjeev S (Author), Sriram, Ganapathy (Author), Lam, Fred C (Author), Patterson, Jesse C (Author), Quadir, Mohiuddin (Author), Dinh, Anh (Author), Shopsowitz, Kevin E (Author), Varmeh, Shohreh (Author), Yilmaz, Ömer H (Author), Lippard, Stephen J (Author), Reinhardt, H Christian (Author), Hemann, Michael T (Author), Hammond, Paula T (Author), Yaffe, Michael B (Author)
• Format: Article
• Language: English
• Published: Springer Science and Business Media LLC, 2021-10-25T17:00:12Z.
• Subjects: Article
• Online Access: Get fulltext

 © 2020, The Author(s). 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.