Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints
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s41467-020-17958-z.pdf
Description
Published version
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2.84 MB
Format
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Checksum (MD5)
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Author(s)
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
Date Issued
2020
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Kong, Yi Wen, Dreaden, Erik C, Morandell, Sandra, Zhou, Wen, Dhara, Sanjeev S et al. 2020. "Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints." Nature Communications, 11 (1).
Version
Final published version
Abstract
© 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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Center for Precision Cancer Medicine
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41467-020-17958-Z
