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Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency.


Maximus Peto’s Commentary

This seems like a clever, if unusual, method of targeting ALT+ cancer cells. This group found that ATRX deficiency “creates a vulnerability” that they exploited by infecting these cells with a mutant herpes simplex virus-1 (HSV-1), which could infect these ALT+ cells “ten- to one thousand-fold more effective[ly] than wild-type ATRX-expressing cells.” Moreover, this mutant HSV-1 “selectively killed ATRX-deficient cells”. I wonder if this might be a technique to target ALT+ cancer cells with a cell-killing virus, while leaving normal cells relatively unaffected.


Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency.
J Cell Sci. 2019 Mar 14;132(5). pii: jcs222349.
Han M, Napier CE, Frölich S, Teber E, Wong T, Noble JR, Choi EHY, Everett RD, Cesare AJ, Reddel RR
DOI: 10.1242/jcs.222349
PubMed publication date (edat): 2/13/2019

Abstract

Cancers that utilize the alternative lengthening of telomeres (ALT) mechanism for telomere maintenance are often difficult to treat and have a poor prognosis. They are also commonly deficient for expression of ATRX protein, a repressor of ALT activity, and a component of promyelocytic leukemia nuclear bodies (PML NBs) that are required for intrinsic immunity to various viruses. Here, we asked whether ATRX deficiency creates a vulnerability in ALT cancer cells that could be exploited for therapeutic purposes. We showed in a range of cell types that a mutant herpes simplex virus type 1 (HSV-1) lacking ICP0, a protein that degrades PML NB components including ATRX, was ten- to one thousand-fold more effective in infecting ATRX-deficient cells than wild-type ATRX-expressing cells. Infection of co-cultured primary and ATRX-deficient cancer cells revealed that mutant HSV-1 selectively killed ATRX-deficient cells. Sensitivity to mutant HSV-1 infection also correlated inversely with PML protein levels, and we showed that ATRX upregulates PML expression at both the transcriptional and post-transcriptional levels. These data provide a basis for predicting, based on ATRX or PML levels, which tumors will respond to a selective oncolytic herpesvirus.

PMID: 30745338
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432714/

Maximus Peto

Max Peto is a longevity researcher and founder of Long Life Labs. A biochemist by training, he studies the biochemistry of aging and longevity and has worked with research organizations such as SENS Research Foundation, Methuselah Foundation, BioAge Labs, Life Extension Foundation, and Ichor Therapeutics. His work at Long Life Labs is focused on empowering people to understand and manage the most critical factors for better health and longer life.

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