Abstract A22: Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency

In human somatic cells, telomeres shorten every cell division due to the end replication problem. Once reaching a critically short length, the cells will undergo permanent cell cycle arrest and become senescent. Cancer cells acquire unlimited proliferation ability by activation of a telomere maintenance mechanism, either the enzyme telomerase or the homologous recombination-based mechanism Alternative Lengthening of Telomeres (ALT). Cancers that utilize the ALT mechanism commonly are deficient for ATRX protein expression, are difficult to treat, and have a poor prognosis. We discovered that ICP0-null herpes simplex virus type 1 (HSV-1) was ten to one thousand-fold more effective in killing cancer cell lines that are ATRX-deficient. Sensitivity to mutant HSV-1 infection resulted from ATRX-dependent regulation of PML expression at both the transcriptional and post-transcriptional levels. Reduction of PML protein resulted in a concomitant reduction in PML nuclear bodies, which weakened the innate cellular immunity to viral infection. Infection of co-cultured primary and ATRX-null cancer cells revealed that mutant ICP0-null HSV-1 treatment preferentially killed ATRX-null cells. Our results suggest that mutant ICP0-null HSV-1 may have therapeutic benefit against ATRX-null cells. Moreover, these data provide an applicable approach for predicting, based on tumor ATRX or PML protein status, which tumors will respond to an oncolytic herpes virus. Citation Format: Mingqi Han, Christine E. Napier, Sonja Frolich, Roger D. Everett, Anthony J. Cesare, Roger R. Reddel. Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A22.