Abstract IA03: Systems approaches reveal shared pathways affected in SARS-CoV-2 infection and cancer
Authors: Krogan Nevan 
Published: December 2020

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, has infected millions and killed hundreds of thousands of people worldwide. Clinicians are fighting the battle against the virus with a limited arsenal of drugs that have been shown to be safe and efficacious in treating SARS-CoV-2 infection. We thus rely on gaining a deeper understanding of the molecular mechanisms of this virus, and desperately need new strategies to get drugs to patients in need quickly. To combine both of these aims, my lab has focused much of our recent work on applying systems biology approaches to identify the cellular pathways hijacked by SARS-CoV-2, with the aim of pinpointing promising clinically available drugs for rapid repurposing to treat COVID-19. Identifying which cellular pathways and mechanisms are affected across different diseases will open the existing toolbox of drug treatment for COVID-19. Cancer drugs are a particularly promising set of drugs in this regard: During the process of virus replication, viruses rely on a multitude of interactions with their host cell, and hijack similar pathways that are affected in cancer cells. For example, viruses manipulate the cell cycle for their own benefit, recruit host DNA-damage machinery to viral replication sites, rely on the host translation machinery for viral protein production, and interfere with several signaling pathways, for example, to suppress cellular antiviral defenses. This list, while not comprehensive, makes apparent the commonalities between the exploitation of molecular mechanisms by cancer and virus infection. To get a full picture of cellular pathways targeted by SARS-CoV-2, we recently generated two virus-host interaction networks using systems biology approaches. First, we used affinity-purification mass spectrometry to create a virus-host protein-protein interaction (PPI) map. We cloned, tagged, and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins and complexes that physically associate with the individual viral proteins. Our map revealed 332 high-confidence PPIs with human proteins involved in a wide spectrum of cell biology, highlighting several oncogenic pathways. We identified 66 druggable human proteins at the virus-host interface, targeted by 69 compounds (of which 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials, and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found that, for example, inhibitors of mRNA translation displayed antiviral activity. In a separate study building on these results, we created a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in cell culture. Focusing on phosphorylation events, which are also highly misregulated in cancer, showed stark changes for both host and viral proteins and revealed dramatic rewiring of a number of signaling pathways. For example, SARS-CoV 2 infection promoted casein kinase II (CK2) and p38 MAP kinase activation and shutdown of mitotic kinases. We identified 87 drugs and compounds by mapping global phosphorylation profiles to dysregulated kinases and pathways. Pharmacologic inhibition of p38, CK2, CDKs, AXL, and PIKFYVE kinases possessed antiviral efficacy, representing potential COVID-19 therapies. Clinical trials with some drugs and compounds implicated by our studies are currently being discussed or are already under way. To prepare for future outbreaks, we need to further increase our knowledge of cellular pathways targeted during virus infection. To this end, in addition to a number of infectious agents my lab has studied previously, we are currently performing similar studies on the closely related coronaviruses responsible for outbreaks of SARS and Middle East respiratory syndrome (MERS) in 2003 and 2012, respectively. Combined with the results discussed above, we hope to position the health care community to successfully fight this and potential future outbreaks of novel infectious diseases. Importantly, the input of physicians and experts from other fields will be crucial to leverage the knowledge gained from our studies about the pathways targeted across diseases.
Citation Format: Nevan Krogan. Systems approaches reveal shared pathways affected in SARS-CoV-2 infection and cancer [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr IA03.