Systems approaches reveal sharedpathways affected in SARS-CoV-2 infection and cancer
Authors: Nevan Krogan
Journal: Clinical Cancer Research (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease2019 (COVID-19) pandemic, has infected millions and killed hundreds of thousands of people worldwide  Cliniciansare fighting the battle against the virus with a limited arsenal of drugs that have been shown to be safe andefficacious in treating SARS-CoV-2 infection  We thus rely on gaining a deeper understanding of the molecularmechanisms of this virus, and desperately need new strategies to get drugs to patients in need quickly  To combineboth of these aims, my lab has focused much of our recent work on applying systems biology approaches to identifythe cellular pathways hijacked by SARS-CoV-2, with the aim of pinpointing promising clinically available drugs forrapid repurposing to treat COVID-19  Identifying which cellular pathways and mechanisms are affected acrossdifferent diseases will open the existing toolbox of drug treatment for COVID-19  Cancer drugs are a particularlypromising set of drugs in this regard: During the process of virus replication, viruses rely on a multitude ofinteractions with their host cell, and hijack similar pathways that are affected in cancer cells  For example, virusesmanipulate the cell cycle for their own benefit, recruit host DNA-damage machinery to viral replication sites, rely onthe host translation machinery for viral protein production, and interfere with several signaling pathways, forexample, to suppress cellular antiviral defenses  This list, while not comprehensive, makes apparent thecommonalities between the exploitation of molecular mechanisms by cancer and virus infection  To get a full pictureof cellular pathways targeted by SARS-CoV-2, we recently generated two virus-host interaction networks usingsystems 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 cellsand identified the human proteins and complexes that physically associate with the individual viral proteins  Our maprevealed 332 high-confidence PPIs with human proteins involved in a wide spectrum of cell biology, highlightingseveral oncogenic pathways  We identified 66 druggable human proteins at the virus-host interface, targeted by 69compounds (of which 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials, and28 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 aquantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in cell culture  Focusingon phosphorylation events, which are also highly misregulated in cancer, showed stark changes for both host andviral proteins and revealed dramatic rewiring of a number of signaling pathways  For example, SARS-CoV 2infection promoted casein kinase II (CK2) and p38 MAP kinase activation and shutdown of mitotic kinases  Weidentified 87 drugs and compounds by mapping global phosphorylation profiles to dysregulated kinases andpathways  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 studiesare currently being discussed or are already under way  To prepare for future outbreaks, we need to further increaseour knowledge of cellular pathways targeted during virus infection  To this end, in addition to a number of infectiousagents my lab has studied previously, we are currently performing similar studies on the closely relatedcoronaviruses 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 tosuccessfully fight this and potential future outbreaks of novel infectious diseas s  Importantly, the input of physiciansand experts from other fields will be crucial to leverage the knowledge gained from our studies about the pathwaystargeted across diseases