Abstract
NSCLC (non-small cell lung cancer) is a leading cause of cancer-related deaths worldwide. Clinical trials showed that Hiltonol, a stable dsRNA representing an advanced form of polyI:C (polyinosinic-polycytidilic acid), is an adjuvant cancer-immunomodulator. However, its mechanisms of action and effect on lung cancer have not been explored pre-clinically. Here, we examined, for the first time, how a novel Hiltonol cocktail kills NSCLC cells. By retrospective analysis of NSCLC patient tissues obtained from the tumor biobank; pre-clinical studies with Hiltonol alone or Hiltonol+++ cocktail [Hiltonol+anti-IL6+AG490 (JAK2 inhibitor)+Stattic (STAT3 inhibitor)]; cytokine analysis; gene knockdown and gain/loss-of-function studies, we uncovered the mechanisms of action of Hiltonol+++. We demonstrated that Hiltonol+++ kills the cancer cells and suppresses the metastatic potential of NSCLC through: (i) upregulation of pro-apoptotic Caspase-9 and Caspase-3, (ii) induction of cytosolic cytochrome c, (iii) modulation of pro-inflammatory cytokines (GRO, MCP-1, IL-8, and IL-6) and anticancer IL-24 in NSCLC subtypes, and (iv) upregulation of tumor suppressors, PKR (protein kinase R) and OAS (2′5′ oligoadenylate synthetase). In silico analysis showed that Lys296 of PKR and Lys66 of OAS interact with Hiltonol. These Lys residues are purportedly involved in the catalytic/signaling activity of the tumor suppressors. Furthermore, knockdown of PKR/OAS abrogated the anticancer action of Hiltonol, provoking survival of cancer cells. Ex vivo analysis of NSCLC patient tissues corroborated that loss of PKR and OAS is associated with cancer advancement. Altogether, our findings unraveled the significance of studying tumor biobank tissues, which suggests PKR and OAS as precision oncological suppressor candidates to be targeted by this novel Hiltonol+++ cocktail which represents a prospective drug for development into a potent and tailored therapy for NSCLC subtypes.
Highlights
Lung cancer is a leading cause of cancer deaths worldwide [1], with metastasis being the main driving force of fatality [2]
Lung cancer cells have been shown to be susceptible to polyI:C combined with inhibitors of IL6 and JAK2/STAT3 [3]
We observed that Hiltonol+++ (Hiltonol in combination with inhibitors of IL6, JAK2, STAT3) significantly suppressed the viability of lung cancer cells compared to Hiltonol alone (Figure 1B)
Summary
Lung cancer is a leading cause of cancer deaths worldwide [1], with metastasis being the main driving force of fatality [2]. There is urgency to identify specific regulators and to understand how they might mediate anticancer effects and cell death in NSCLC cells, with a view to developing precision diagnostics and targeted cancer therapeutics. Hiltonol has only been applied as an investigational adjuvant to stimulate immune cells such as CD8-T cells and dendritic cells in cancer patients. This is despite recent clinical trial on lung cancer patients (https://immuno-oncologynews.com/2018/05/29/first-lung-cancer-patienttreated-with-neo-pv-01-phase-1-trial/ (accessed on 6 October 2020)), which was designed to evaluate the safety and tolerability of NEO-PV-01, administered alongside Hiltonol, Keytruda, and Alimta (pemetrexed) and Paraplatin (carboplatin)
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