Research Article: Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis

Date Published: August 23, 2018

Publisher: Public Library of Science

Author(s): Chadi Zakaria, Polen Sean, Huy-Dung Hoang, Louis-Phillipe Leroux, Margaret Watson, Samuel Tekeste Workenhe, Jaclyn Hearnden, Dana Pearl, Vinh Tai Truong, Nathaniel Robichaud, Akiko Yanagiya, Soroush Tahmasebi, Seyed Mehdi Jafarnejad, Jian-Jun Jia, Adrian Pelin, Jean-Simon Diallo, Fabrice Le Boeuf, John Cameron Bell, Karen Louise Mossman, Tyson Ernst Graber, Maritza Jaramillo, Nahum Sonenberg, Tommy Alain, Dirk P. Dittmer.


Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells. Surprisingly, using the infected cell protein 0 (ICP0)-deleted HSV1 (HSV1-dICP0), we found that asTORi markedly augment infection in cancer cells and a mouse mammary cancer xenograft. Mechanistically, asTORi repressed mRNA translation in normal cells, resulting in defective antiviral response but also inhibition of HSV1-dICP0 replication. asTORi also reduced antiviral response in cancer cells, however in contrast to normal cells, transformed cells and cells transduced to elevate the expression of eukaryotic initiation factor 4E (eIF4E) or to silence the repressors eIF4E binding proteins (4E-BPs), selectively maintained HSV1-dICP0 protein synthesis during asTORi treatment, ultimately supporting increased viral replication. Our data show that altered eIF4E/4E-BPs expression can act to promote HSV1-dICP0 infection under prolonged mTOR inhibition. Thus, pharmacoviral combination of asTORi and HSV1 can target cancer cells displaying dysregulated eIF4E/4E-BPs axis.

Partial Text

Oncolytic viruses are promising immunotherapeutic agents for the treatment of cancer [1]. HSV1 application is amongst the most advanced and successful oncolytic platforms; with Amgen’s oncolytic HSV1 talimogene laherparepvec (T-Vec, Imlygic) being the first oncolytic virus to receive FDA and EMA (Food and Drug Administration and European Medicines Agency) approval in October 2015 [2]. Numerous groups are developing oncolytic HSV1 variants, including the pre-clinical development of an infected-cell-protein-0-deleted HSV1 (HSV1-dICP0) [3]. Rapid viral clearance within tumour tissues constitutes a limitation for oncolytic viral therapies. Thus, potentiating viral replication could further increase efficacy [4].

In this study we investigated the pharmacoviral combination of asTORi and HSV1-dICP0. asTORi treatment suppressed type-I IFN responses in normal and cancer cells. The treatment impaired the replication of HSV1-dICP0 in non-transformed cells, but infection was strikingly augmented in cancer cells. Furthermore, in an aggressive syngeneic mammary cancer mouse model, the combination of asTORi and HSV1-dICP0 reduced tumour size and prolonged survival compared to either monotherapy. Mechanistically our data show that asTORi treatment initially represses global mRNA translation, but HSV1-dICP0 protein expression persists in cancer cells and cells with dysregulated eIF4E/4E-BP ratio. Since cancer cells with high eIF4E expression demonstrate resistance to the anti-proliferative effects of asTORi [23], combining dual mTORC1 and 2 inhibitors with HSV1-dICP0 could potentially provide the selective advantage of increasing viral oncolysis of mTOR-inhibitor resistant cancer cells.