Universität zu Köln

Kong, Yi Wen, Dreaden, Erik C., Morandell, Sandra, Zhou, Wen, Dhara, Sanjeev S., Sriram, Ganapathy, Lam, Fred C., Patterson, Jesse C., Quadir, Mohiuddin, Shopsowitz, Kevin E., Varmeh, Shohreh, Yilmaz, Omer H., Lippard, Stephen J., Reinhardt, H. Christian, Hemann, Michael T., Hammond, Paula T. and Yaffe, Michael B. (2020). Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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. Cell cycle checkpoint kinase, MK2, is in synthetic relationship with p53 in the DNA damage response to chemotherapeutic agents. Here, the authors report XPA as a third gene in which simultaneous targeting of MK2 and XPA further enhances sensitivity to cisplatin in p53-deficient tumours.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kong, Yi Wen UNSPECIFIED UNSPECIFIED UNSPECIFIED Dreaden, Erik C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Morandell, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhou, Wen UNSPECIFIED UNSPECIFIED UNSPECIFIED Dhara, Sanjeev S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sriram, Ganapathy UNSPECIFIED UNSPECIFIED UNSPECIFIED Lam, Fred C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Patterson, Jesse C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Quadir, Mohiuddin UNSPECIFIED UNSPECIFIED UNSPECIFIED Shopsowitz, Kevin E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Varmeh, Shohreh UNSPECIFIED UNSPECIFIED UNSPECIFIED Yilmaz, Omer H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lippard, Stephen J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, H. Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hemann, Michael T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hammond, Paula T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yaffe, Michael B. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-323129
DOI:	10.1038/s41467-020-17958-z
Journal or Publication Title:	Nat. Commun.
Volume:	11
Number:	1
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE RESPONSE; CROSS-LINK REPAIR; LUNG-CANCER; OVARIAN-CANCER; PROTEIN; KINASE; CISPLATIN; TUMORS; P53; INHIBITOR Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32312