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

Kong, Yi Wen; Dreaden, Erik C; Morandell, Sandra; Zhou, Wen; Dhara, Sanjeev S; Sriram, Ganapathy; Lam, Fred C; 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

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.