Machine learning identifies molecular regulators and therapeutics for targeting SARS-CoV2-induced cytokine release.

Although 15-20% of COVID-19 patients experience hyper-inflammation induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N-terminal domain (NTD) of the SARS-CoV-2 spike protein substantially induces multiple inflammatory molecules in myeloid cells and human PBMCs. Using a combination of phenotypic screening with machine learning-based modeling, we identified and experimentally validated several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as essential downstream mediators of NTD-induced cytokine production, implicating the role of multiple signaling pathways in cytokine release. Further, we found several FDA-approved drugs, including ponatinib, and cobimetinib as potent inhibitors of the NTD-mediated cytokine release. Treatment with ponatinib outperforms other drugs, including dexamethasone and baricitinib, inhibiting all cytokines in response to the NTD from SARS-CoV-2 and emerging variants. Finally, ponatinib treatment inhibits lipopolysaccharide-mediated cytokine release in myeloid cells in vitro and lung inflammation mouse model. Together, we propose that agents targeting multiple kinases required for SARS-CoV-2-mediated cytokine release, such as ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19.

Deep neural network modeling identifies biomarkers of response to immune-checkpoint therapy.

Immunotherapy has shown significant promise as a treatment for cancer, such as lung cancer and melanoma. However, only 10%-30% of the patients respond to treatment with immune checkpoint blockers (ICBs), underscoring the need for biomarkers to predict response to immunotherapy. Here, we developed DeepGeneX, a computational framework that uses advanced deep neural network modeling and feature elimination to reduce single-cell RNA-seq data on ∼26,000 genes to six of the most important genes (CCR7, SELL, GZMB, WARS, GZMH, and LGALS1), that accurately predict response to immunotherapy. We also discovered that the high LGALS1 and WARS-expressing macrophage population represent a biomarker for ICB therapy nonresponders, suggesting that these macrophages may be a target for improving ICB response. Taken together, DeepGeneX enables biomarker discovery and provides an understanding of the molecular basis for the model's predictions.

Non-linear Deep Neural Network for Rapid and Accurate Prediction of Phenotypic Responses to Kinase Inhibitors.

Protein kinase inhibitors are one of the most successful targeted therapies to date. Despite this progress, additional kinase inhibitors are needed to expand the target space as well as overcome drug resistance that has emerged in clinical setting. Here, we developed KiDNN (Kinase inhibitor prediction using Deep Neural Networks). KiDNN utilizes non-linear, multilayer feedforward network that mimics complex and dynamic kinase-driven signaling pathways. We used KiDNN to predict the effect of ∼200 kinase inhibitors on migration of breast and liver cancer cells. We show that the prediction accuracy of KiDNN outperformed other prediction tools based on linear models. We validated that an inhibitor of tyrosine kinase receptors, and an inhibitor of Src family kinases, decreased migration of triple-negative breast cancer cells, consistent with the role of these kinases in driving motility. Overall, we show that non-linear, DNN-based models provide a powerful approach to in silico screen hundreds of kinase inhibitors.