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
PubMed publication date (edat): 2/13/2019
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.
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432714/