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

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

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17958-z

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