TY - JOUR
T1 - Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments
AU - Ma, Jiacheng
AU - Goodwani, Sunil
AU - Acton, Paul J.
AU - Buggia-Prevot, Virginie
AU - Kesler, Shelli R.
AU - Jamal, Imran
AU - Mahant, Iteeben D.
AU - Liu, Zhen
AU - Mseeh, Faika
AU - Roth, Bruce L.
AU - Chakraborty, Chaitali
AU - Peng, Bo
AU - Wu, Qi
AU - Jiang, Yongying
AU - Le, Kang
AU - Soth, Michael J.
AU - Jones, Philip
AU - Kavelaars, Annemieke
AU - Ray, William J.
AU - Heijnen, Cobi Jacoba Johanna
N1 - Funding Information:
The work was supported by generous philanthropic donations to the Neurodegeneration Consortium, grant 20160903 from the Alzheimer Drug Discovery Foundation (Ray), and grants CA208371 (C.J.H. and A.K.), NS073939 (A.K. and C.J.H.), and CA227064 (A.K. and C.J.H.) from the National Institutes of Health. The RNA sequencing work was done with technical support from The University of Texas MD Anderson Cancer Center's Sequencing and Microarray Facility, supported by The University of Texas MD Anderson Cancer Center Support Grant NIH CA016672.
Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairments (CICI) are common, often severe neurotoxic side effects of cancer treatment that greatly reduce quality of life of cancer patients and survivors. Currently, there are no Food and Drug Administration-approved agents for the prevention or curative treatment of CIPN or CICI. The dual leucine zipper kinase (DLK) is a key mediator of axonal degeneration that is localized to axons and coordinates the neuronal response to injury. We developed a novel brain-penetrant DLK inhibitor, IACS′8287, which demonstrates potent and highly selective inhibition of DLK in vitro and in vivo. Coadministration of IACS′8287 with the platinum derivative cisplatin prevents mechanical allodynia, loss of intraepidermal nerve fibers in the hind paws, cognitive deficits, and impairments in brain connectivity in mice, all without interfering with the antitumor activity of cisplatin. The protective effects of IACS′8287 are associated with preservation of mitochondrial function in dorsal root ganglion neurons and in brain synaptosomes. In addition, RNA sequencing analysis of dorsal root ganglia reveals modulation of genes involved in neuronal activity and markers for immune cell infiltration by DLK inhibition. These data indicate that CIPN and CICI require DLK signaling in mice, and DLK inhibitors could become an attractive treatment in the clinic when coadministered with cisplatin, and potentially other chemotherapeutic agents, to prevent neurotoxicities as a result of cancer treatment.
AB - Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairments (CICI) are common, often severe neurotoxic side effects of cancer treatment that greatly reduce quality of life of cancer patients and survivors. Currently, there are no Food and Drug Administration-approved agents for the prevention or curative treatment of CIPN or CICI. The dual leucine zipper kinase (DLK) is a key mediator of axonal degeneration that is localized to axons and coordinates the neuronal response to injury. We developed a novel brain-penetrant DLK inhibitor, IACS′8287, which demonstrates potent and highly selective inhibition of DLK in vitro and in vivo. Coadministration of IACS′8287 with the platinum derivative cisplatin prevents mechanical allodynia, loss of intraepidermal nerve fibers in the hind paws, cognitive deficits, and impairments in brain connectivity in mice, all without interfering with the antitumor activity of cisplatin. The protective effects of IACS′8287 are associated with preservation of mitochondrial function in dorsal root ganglion neurons and in brain synaptosomes. In addition, RNA sequencing analysis of dorsal root ganglia reveals modulation of genes involved in neuronal activity and markers for immune cell infiltration by DLK inhibition. These data indicate that CIPN and CICI require DLK signaling in mice, and DLK inhibitors could become an attractive treatment in the clinic when coadministered with cisplatin, and potentially other chemotherapeutic agents, to prevent neurotoxicities as a result of cancer treatment.
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U2 - 10.1097/j.pain.0000000000002256
DO - 10.1097/j.pain.0000000000002256
M3 - Article
C2 - 33872235
AN - SCOPUS:85113741105
SN - 0304-3959
VL - 162
SP - 2599
EP - 2612
JO - Pain
JF - Pain
IS - 10
ER -