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

Area of Science:

• Oncolytic virotherapy
• Cancer biology
• Telomere maintenance

Background:

• Alternative Lengthening of Telomeres (ALT) cancers are treatment-resistant with poor prognoses.
• These cancers often lack ATRX protein, a repressor of ALT activity and a key component of promyelocytic leukemia nuclear bodies (PML NBs).
• PML NBs are crucial for intrinsic immunity against viral infections.

Purpose of the Study:

• To investigate if ATRX deficiency in ALT cancer cells presents a therapeutic vulnerability.
• To explore the potential of a modified herpes simplex virus type 1 (HSV-1) as an oncolytic agent against ALT cancers.

Main Methods:

• Utilized a mutant HSV-1 lacking the ICP0 protein, which degrades PML NB components including ATRX.
• Tested the infectivity and selectivity of the mutant HSV-1 in various cell types, including co-cultures of primary and ATRX-deficient cancer cells.
• Assessed the correlation between cancer cell sensitivity to mutant HSV-1 and ATRX or PML protein levels.

Main Results:

• Mutant HSV-1 showed a 10- to 1000-fold increased efficacy in infecting ATRX-deficient cells compared to wild-type ATRX-expressing cells.
• The mutant HSV-1 selectively killed ATRX-deficient cancer cells in co-cultured environments.
• Sensitivity to mutant HSV-1 infection inversely correlated with promyelocytic leukemia (PML) protein levels.
• Demonstrated that ATRX upregulates PML expression at both transcriptional and post-transcriptional levels.

Conclusions:

• ATRX deficiency creates a specific vulnerability in ALT cancer cells exploitable by ICP0-mutant HSV-1.
• The findings suggest that ICP0-mutant HSV-1 can serve as a selective oncolytic virus against ATRX-deficient ALT cancers.
• Tumor ATRX and PML protein levels can predict patient response to this novel oncolytic herpesvirus therapy.