Association of Antineoplastic Therapy With Decreased SARS-CoV-2 Infection Rates in Patients With Cancer | Clinical Pharmacy and Pharmacology | JAMA Oncology | JAMA Network
[Skip to Navigation]
Sign In
Figure 1.  Identification of Compounds Associated With a Reduced ACE2 Gene Expression Signature in the LINCS Data Set
Identification of Compounds Associated With a Reduced ACE2 Gene Expression Signature in the LINCS Data Set

A total of 1835 compounds and their respective ACE2 gene expression signature coefficients (negative value indicates reduced expression; positive value, increased expression) obtained from the Library of Integrated Network-Based Cellular Signatures (LINCS) data set are each represented by circles. Circles are colored according to drug mechanism of action. The y-axis indicates the negative log of the false discovery rate (FDR)-adjusted P value associated with each compound’s ACE2 gene signature. Antineoplastics associated with an FDR-adjusted P ≤ .10 in the LINCS analysis (dotted horizontal line cutoff) also given to patients in the clinical cohort are represented in the zoomed-in partition.

Figure 2.  Association Between Patient Characteristics and SARS-CoV-2 Positivity in Univariable and Multivariable Analyses
Association Between Patient Characteristics and SARS-CoV-2 Positivity in Univariable and Multivariable Analyses

Odds ratios for a positive SARS-CoV-2 test are represented for the second covariate subgroup in comparison with the first covariate subgroup. False discovery rate (FDR)-adjusted P values are represented after Benjamini-Hochberg correction for multiplicity (A), and all covariates were placed into a multivariable logistic regression model (B), except smoking status owing to excessive missing data (233 of 1701 patients). Patients with unspecified race and ethnicity were not included in the multivariable analysis (56 of 1701 patients).

Table.  Characteristics of the Clinical Cohort
Characteristics of the Clinical Cohort
1.
Hoffmann  M, Kleine-Weber  H, Schroeder  S,  et al.  SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.   Cell. 2020;181(2):271-280.e8. doi:10.1016/j.cell.2020.02.052PubMedGoogle ScholarCrossref
2.
Wei  J, Alfajaro  MM, DeWeirdt  PC,  et al.  Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection.   Cell. 2021;184(1):76-91.e13. doi:10.1016/j.cell.2020.10.028PubMedGoogle ScholarCrossref
3.
Walls  AC, Park  YJ, Tortorici  MA, Wall  A, McGuire  AT, Veesler  D.  Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.   Cell. 2020;181(2):281-292.e6. doi:10.1016/j.cell.2020.02.058PubMedGoogle ScholarCrossref
4.
Jee  J, Foote  MB, Lumish  M,  et al.  Chemotherapy and COVID-19 outcomes in patients with cancer.   J Clin Oncol. 2020;38(30):3538-3546. doi:10.1200/JCO.20.01307PubMedGoogle ScholarCrossref
5.
Zoufaly  A, Poglitsch  M, Aberle  JH,  et al.  Human recombinant soluble ACE2 in severe COVID-19.   Lancet Respir Med. 2020;8(11):1154-1158. doi:10.1016/S2213-2600(20)30418-5PubMedGoogle ScholarCrossref
6.
Lei  C, Qian  K, Li  T,  et al.  Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig.   Nat Commun. 2020;11(1):2070. doi:10.1038/s41467-020-16048-4PubMedGoogle ScholarCrossref
7.
Dyall  J, Coleman  CM, Hart  BJ,  et al.  Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection.   Antimicrob Agents Chemother. 2014;58(8):4885-4893. doi:10.1128/AAC.03036-14PubMedGoogle ScholarCrossref
8.
Roschewski  M, Lionakis  MS, Sharman  JP,  et al.  Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.   Sci Immunol. 2020;5(48):eabd0110. doi:10.1126/sciimmunol.abd0110PubMedGoogle Scholar
9.
Singh  TU, Parida  S, Lingaraju  MC, Kesavan  M, Kumar  D, Singh  RK.  Drug repurposing approach to fight COVID-19.   Pharmacol Rep. 2020;72(6):1479-1508. doi:10.1007/s43440-020-00155-6PubMedGoogle ScholarCrossref
10.
Karam  BS, Morris  RS, Bramante  CT,  et al.  mTOR inhibition in COVID-19: a commentary and review of efficacy in RNA viruses.   J Med Virol. 2021;93(4):1843-1846. doi:10.1002/jmv.26728PubMedGoogle ScholarCrossref
11.
Kindrachuk  J, Ork  B, Hart  BJ,  et al.  Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis.   Antimicrob Agents Chemother. 2015;59(2):1088-1099. doi:10.1128/AAC.03659-14PubMedGoogle ScholarCrossref
12.
Appelberg  S, Gupta  S, Svensson Akusjärvi  S,  et al.  Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells.   Emerg Microbes Infect. 2020;9(1):1748-1760. doi:10.1080/22221751.2020.1799723PubMedGoogle ScholarCrossref
13.
Zhou  Y, Hou  Y, Shen  J, Huang  Y, Martin  W, Cheng  F.  Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2.   Cell Discov. 2020;6(1):14. doi:10.1038/s41421-020-0153-3PubMedGoogle ScholarCrossref
14.
Keenan  AB, Jenkins  SL, Jagodnik  KM,  et al.  The Library of Integrated Network-Based Cellular Signatures NIH program: system-level cataloging of human cells response to perturbations.   Cell Syst. 2018;6(1):13-24. doi:10.1016/j.cels.2017.11.001PubMedGoogle ScholarCrossref
15.
Duarte  MBO, Leal  F, Argenton  JLP, Carvalheira  JBC.  Outcomes of COVID-19 patients under cytotoxic cancer chemotherapy in Brazil.   Cancers (Basel). 2020;12(12):E3490. doi:10.3390/cancers12123490PubMedGoogle Scholar
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    2 Comments for this article
    EXPAND ALL
    In the COVID-19 era, importance of prescribing ACE2-lowering antineoplastics
    takuma hayashi, MBBS, DMSci, GMRC, PhD | National Hospital Organization Kyoto Medical Center
    Foote et al. reported that patients who received a potential ACE2-lowering antineoplastic exhibited a statistically significantly reduced SARS-CoV-2 positivity rate of 7.0% compared with 12.9% in patients who received other antineoplastic therapies. Potential ACE2-lowering antineoplastics, including mTOR/PI3K inhibitors and antimetabolites, may exhibit clinical anti–SARS-CoV-2 activity.

    In the current COVID-19 era, the results of clinical studies reported by Foote et al. are very interesting and important.

    Cancer treatment is performed by first-line treatment, second-line treatment, and third-line treatment according to clinical practice guidelines for each cancer type. Therefore, an appropriate antitumor agent is prescribed according to the progress of
    each cancer type and the patient's medical history. Until now, in clinical practice, antitumor agents for each cancer type have not been selected while considering ACE2-lowering antineoplastics.

    Currently, personalized medicine by cancer genome test is performed in cancer treatment all over the world. In Japan as well, the Cancer Genome Panel Test (NCC oncopanel, FoundationOne CDx) was covered by health insurance on June 1, 2019. Therefore, in Japan, from the end of 2019, personalized medicine by cancer genome test has been performed.

    From January 2020 to July 2021, personalized medical care by cancer genome testing is being performed for about 850 cancer patients at national university hospitals in Japan. ACE2-lowering antineoplastics including mTOR/PI3K inhibitors and antimetabolites (i.e., everolimus, temsirolimus, alpelisib, decitabine, gemcitabine, cabazitaxel, dasatinib, crizotinib) were recommended or suggested to 65 cancer patients.

    From the results of clinical trials so far, it has been reported that the anti-SARS-CoV-2 antibody titer induced by second doses of COVID-19 mRNA vaccine is lower in cancer patients than in healthy subjects. In the future, when it is possible to select multiple antitumor drug prescriptions for cancer patients in clinical practice, it might be important to preferentially prescribe ACE2-lowering antineoplastics in consideration of anti-SARS-CoV-2.

    Dr. Takuma Hayashi and Dr. Ikuo Konishi
    National Hospital Organization Kyoto Medical Center
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Great find!
    rob tinder, PhD | Intense Process Technologies
    Despite the overlap in ACE 2 expression inhibition with compounds with antiviral like activity, this work demonstrates an important paradigm for in-silico drug discovery using real world patient data as validation.

    As near as I can find there have been no clinical trials initiated on Gemcitabine for SARS-COV2 despite several reports of gemcitabine activity in vitro against SARS-Cov-2, including synergy with Remdesivir https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915419/. While therapeutic index of such antineoplastics may have created some tunnel vision, this report demonstrates the potential importance of these compounds as potent anti-viral compounds.

    This work shows huge promise in being able to
    find evidence based leads with real world patient data for repurposing drugs, rather than simple in-silico target hunting.

    I hope these efforts continue, and are expanded look at overlap in many areas of medicine.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Views 7,928
    Citations 0
    Brief Report
    August 19, 2021

    Association of Antineoplastic Therapy With Decreased SARS-CoV-2 Infection Rates in Patients With Cancer

    Author Affiliations
    • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    • 2Resphera Biosciences, Baltimore, Maryland
    • 3Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    JAMA Oncol. Published online August 19, 2021. doi:10.1001/jamaoncol.2021.3585
    Key Points

    Question  Will patients with cancer treated with antineoplastic compounds associated with lower angiotensin-converting enzyme 2 (ACE2) expression exhibit lower SARS-CoV-2 infection rates?

    Findings  In an in silico analysis of the Library of Integrated Network-Based Cellular Signatures database, 91 compounds were associated with gene downregulation of the ACE2 entry receptor for SARS-CoV-2, including mTOR/PI3K inhibitors and antimetabolites. Patients who received a potential ACE2-lowering antineoplastic exhibited a statistically significantly reduced SARS-CoV-2 positivity rate of 7.0% compared with 12.9% in patients who received other antineoplastic therapies.

    Meaning  Potential ACE2-lowering antineoplastics, including mTOR/PI3K inhibitors and antimetabolites, may exhibit clinical anti–SARS-CoV-2 activity.

    Abstract

    Importance  Novel therapies for SARS-CoV-2 infection are urgently needed. Antineoplastic compounds that target cellular machinery used by SARS-CoV-2 for entry and replication, including angiotensin-converting enzyme 2 (ACE2), may disrupt SARS-CoV-2 activity.

    Objectives  To determine whether patients with cancer treated with potential ACE2-lowering antineoplastic compounds exhibit lower SARS-CoV-2 infection rates.

    Design, Setting, and Participants  We used the Library of Integrated Network-Based Cellular Signatures database to identify antineoplastic compounds associated with decreased ACE2 gene expression across cell lines. We then evaluated a retrospective cohort of 1701 patients who were undergoing antineoplastic therapy at Memorial Sloan Kettering Cancer Center in New York, New York, during the COVID-19 pandemic to determine if treatment with an ACE2-lowering antineoplastic was associated with a decreased odds ratio (OR) of SARS-CoV-2 infection. Patients included in the analysis underwent active treatment for cancer and received a SARS-CoV-2 test between March 10 and May 28, 2020.

    Main Outcome and Measure  The association between potential ACE2-lowering antineoplastic treatment and a positive SARS-CoV-2 test.

    Results  In the cohort of 1701 patients, SARS-CoV-2 infection rates were determined for 949 (55.8%) female and 752 (44.2%) male patients (mean [SD] age, 63.1 [13.1] years) with diverse cancers receiving antineoplastic therapy. In silico analysis of gene expression signatures after drug treatment identified 91 compounds associated with downregulation of ACE2 across cell lines. Of the total cohort, 215 (12.6%) patients were treated with 8 of these compounds, including 3 mTOR/PI3K inhibitors and 2 antimetabolites. In a multivariable analysis of patients who received an ACE2-lowering antineoplastic adjusting for confounders, 15 of 215 (7.0%) patients had a positive SARS-CoV-2 test compared with 191 of 1486 (12.9%) patients who received other antineoplastic therapies (OR, 0.53; 95% CI, 0.29-0.88). Findings were confirmed in additional sensitivity analyses including cancer type, steroid use, and a propensity-matched subcohort. Gemcitabine treatment was associated with reduced SARS-CoV-2 infection (OR, 0.42; 95% CI, 0.17-0.87).

    Conclusions and Relevance  In this cohort study, in silico analysis of drug-associated gene expression signatures identified potential ACE2-lowering antineoplastic compounds, including mTOR/PI3K inhibitors and antimetabolites. Patients who received these compounds exhibited statistically significantly lower rates of SARS-CoV-2 infection compared with patients given other antineoplastics. Further evaluation of the biological and clinical anti–SARS-CoV-2 properties of identified antineoplastic compounds is warranted.

    Introduction

    SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19.1 SARS-CoV-2 infects host cells by attaching spike glycoproteins to angiotensin-converting enzyme 2 (ACE2), encoded by the ACE2 gene, expressed on airway epithelia.1-3 Hemagglutinin cleavage of ACE2 initiates viral internalization and subsequent viral S protein cleavage through hijacking of cellular machinery.1 Patients with cancer are especially vulnerable to adverse COVID-19 outcomes after SARS-CoV-2 infection.4

    Engineered anti-ACE2 therapies have demonstrated preliminary success as COVID-19 treatments.5,6 Repurposed antineoplastic agents that inhibit proliferative signaling pathways hijacked by SARS-CoV-2 are predicted with in silico and in vitro analyses to inhibit SARS-CoV-2 activity, yet clinical activity is rarely evaluated.7-13

    In this cohort study, we used the Library of Integrated Network-Based Cellular Signatures (LINCS) program to identify antineoplastic compounds associated with decreased ACE2 gene expression in silico.14 We then evaluated if patients with cancer treated with potential ACE2-lowering antineoplastics during the COVID-19 pandemic exhibited decreased incidence of SARS-CoV-2 infection.

    Methods
    In Vitro Modeling and Analysis

    The LINCS program aggregates quality-controlled in vitro compound screens to identify the gene expression profile of a drug across multiple cell lines (eMethods in the Supplement). Using LINCS, we analyzed ACE2 gene expression signatures of 1835 compounds across 7 cell lines with the highest gene expression profiles (MCF7, PC-3, HeLa, HT-29, A-375, HA1E, and YAPC). For each compound, a generalized linear model of ACE2-moderated z scores (weighted average of experimental sample replicates) vs log10(drug concentration) produced model coefficients representing the association between drug treatment and consensus net ACE2 expression change across all cell lines. The Benjamini-Hochberg (BH) method was used to adjust for multiplicity. Antineoplastic compounds associated with both a negative model coefficient (downregulated ACE2 expression) and a BH-adjusted P ≤ .10 were selected for clinical validation.

    Patient Cohort and Analysis

    Electronic medical record data was obtained from a standardized-input database for adult patients at Memorial Sloan Kettering Cancer Center in New York, New York, who were undergoing antineoplastic treatment for active cancer during the COVID-19 pandemic from March 10 through May 28, 2020. All patients included in the study underwent SARS-CoV-2 real-time polymerase chain reaction testing during this period. Antineoplastics given to patients were categorized per standard definitions (eTable 1 in the Supplement). Patients were stratified based on whether they received a compound associated with a reduced ACE2 gene expression signature between March 10 and May 28, 2020. Exploratory clinical outcomes, including hospital admission, hypoxic event (≥3 L of supplemental oxygen required), and death, were compiled. Race and ethnicity were derived from patient selections on standardized forms that were uploaded into the electronic medical records. Groups in the Non-White or Hispanic category included patients who selected East Asian or the Indian subcontinent, Black or African American, American Indian or Alaska Native, and other race. Patients who selected both White and Hispanic in the ethnicity section were included in the Non-White or Hispanic category. Patients who selected White and either non-Hispanic or did not enter a value in ethnicity were categorized as White. This study was approved by the Memorial Sloan Kettering Cancer Center institutional review board with exemption of patient consent secondary to use of deidentified data.

    Statistical Analysis

    The associations between SARS-CoV-2 positivity and study covariates, including ACE2-lowering antineoplastic therapy, were separately evaluated using Fisher exact testing. For univariable analyses, false discovery rate–adjusted P values were obtained using the BH method for multiplicity correction. A multivariable logistic regression model evaluated the association between covariates and SARS-CoV-2 positivity (smoking status was excluded owing to excessive missing data). This process was replicated in additional sensitivity analyses to evaluate alternative LINCS thresholds for ACE2-lowering antineoplastic selection, associations between cancer types among patients, steroid use, or ACE2-inducing antineoplastic use and SARS-CoV-2 infection, and a propensity score–matched subcohort analysis (eMethods in the Supplement). Associations between ACE2-lowering antineoplastic status and clinical outcomes were assessed using Fisher exact testing in the overall study cohort and in patients who tested positive for SARS-CoV-2. Analyses were performed using R, version 4.0.0 (R Foundation for Statistical Computing) (eAppendix in the Supplement).

    Results

    A total of 91 compounds were identified from the LINCS data set (Figure 1 and eTables 2 and 3 in the Supplement) and associated with considerably reduced ACE2 gene expression across cell lines. Of these 91 compounds, 8 were administered in the clinical cohort (Figure 1 and eTables 3 and 4 in the Supplement). Compounds included mTOR/PI3K inhibitors (everolimus, temsirolimus, and alpelisib), antimetabolites (decitabine and gemcitabine), mitotic inhibitors (cabazitaxel), and other kinase inhibitors (dasatinib and crizotinib).

    Of the 1701 patients in the study cohort, 1553 (91.3%) possessed solid tumors, although 394 (23.2%) patients had a hematologic cancer, and 312 (18.3%) patients had more than 1 cancer type (Table and eTable 4 in the Supplement). A total of 215 (12.6%) patients were treated with a potential ACE2-lowering antineoplastic (Table). Patients in the ACE2 treatment subgroups exhibited similar characteristics, although the ACE2-lowering antineoplastic subgroup was composed of both fewer male patients and patients with hematologic cancers (Table and eTable 4 in the Supplement).

    Patients who received an associated ACE2-lowering antineoplastic drug exhibited a statistically significant decreased SARS-CoV-2 positivity rate of 7.0% (15 of 215 patients) compared with a 12.9% rate (191 of 1486 patients) in those not treated with an ACE2-lowering antineoplastic in a multivariable analysis (odds ratio [OR], 0.53; 95% CI, 0.29-0.88; Figure 2). This association was consistent in sensitivity analyses that used different LINCS data set significance thresholds to select ACE2-lowering antineoplastics (eTable 5 in the Supplement), as well as separate multivariable analyses that included specific patient cancer types (eTable 6 in the Supplement) or steroid use (eTable 7 in the Supplement), and a propensity score–matched multivariable regression sensitivity analysis that analyzed paired patients based on multiple characteristics (eTable 8 in the Supplement). Non-White or Hispanic patients with cancer exhibited increased SARS-CoV-2 infections compared with White non-Hispanic patients (OR, 1.78; 95% CI, 1.28-2.45).

    In the primary analysis, use of gemcitabine was associated with decreased SARS-CoV-2 positivity (OR, 0.42; 95% CI, 0.17-0.87; eTable 9 in the Supplement). Use of ACE2-lowering antineoplastics was not statistically significantly associated with hospital admission, hypoxic event, or death in the overall cohort (eTable 10A in the Supplement) or SARS-CoV-2 positive–only subcohort (eTable 10B in the Supplement).

    Discussion

    This study used a genomic data set to identify antineoplastic compounds associated with modulation of infectious disease–related gene expression. In a large cohort with diverse cancer and treatment histories, patients who received potential ACE2-lowering antineoplastics were nearly half as likely to have positive results for SARS-CoV-2 compared with patients treated with other active antineoplastic therapies (Figure 2). This finding remained consistent after accounting for confounders in multivariable and propensity score–matched analyses (Figure 2B and eTables 5-8 in the Supplement). Examination of each study drug shows that the majority of associated ACE2-lowering antineoplastics (6 of 8) were associated with at least an absolute 3% reduction in SARS-CoV-2 positivity (eTable 9 in the Supplement). Although individual drug analyses were likely underpowered, patients given gemcitabine demonstrated statistically significant lower SARS-CoV-2 positivity rates compared with patients given other antineoplastics (eTable 9 in the Supplement).

    The ACE2-lowering compounds may alter SARS-CoV-2 activity through ACE2-downregulation and/or other plausible antiviral mechanisms. Most associated ACE2-lowering compounds target internal cellular machinery responsible for proliferation and metabolism, similar to kinase inhibitors targeting BCR-ABL, Janus kinase 1 and 2, and Bruton tyrosine kinase currently under clinical validation.8,9 Everolimus, temsirolimus, and alpelisib inhibit the viral mTOR/PI3K signaling pathway that modulates immune signaling and coronavirus-family viral protein activity in vitro.10-12 In addition, use of gemcitabine and dasatinib has been shown in vitro to considerably inhibit coronavirus-family viral activity.7 Gemcitabine and decitabine exhibit similar antimetabolic activity to that of 6-mercaptopurine, which is identified as a SARS-CoV-2 protein inhibitor.13 Antimetabolite use has been associated with lower COVID-19–related mortality in patients with cancer.15

    Limitations

    This study identifies novel antineoplastic compounds that may impede SARS-CoV-2 activity and subsequently demonstrates a clinical association between compound administration and reduced SARS-CoV-2 infection in a large cohort of at-risk patients with cancer. However, the study has several limitations. Although patients who tested positive for SARS-CoV-2 infection who were given ACE2-lowering antineoplastics exhibited decreased hospital admissions and hypoxic events, these associations were not statistically significant, potentially because of low numbers of observed events (eTable 10 in the Supplement). Mortality from active cancer vs SARS-CoV-2 infection was also difficult to assess. The ACE2-lowering antineoplastics were discovered by computer modeling of in vitro data. Compound mechanism of activity against SARS-CoV-2 is not fully characterized and requires experimental validation, particularly with testing in respiratory epithelial cell lines, which are not well represented in LINCS. Potential protective effects from ACE2-lowering antineoplastics must also be taken in the context of additional immune protection advances that occurred poststudy, including vaccination. The study is hypothesis generating and serves to direct further experimental exploration of the molecular mechanisms underlying anti–SARS-CoV-2 activity for potential ACE2-lowering antineoplastic agents.

    Conclusions

    In this cohort study, mTOR/PI3K inhibitors and antimetabolites were among several antineoplastic compounds associated with decreased ACE2 gene expression in silico. Patients with cancer treated with predicted ACE2-lowering antineoplastics exhibited statistically significant lower incidence of SARS-CoV-2 infection compared with patients who received other therapies.

    Back to top
    Article Information

    Accepted for Publication: June 17, 2021.

    Published Online: August 19, 2021. doi:10.1001/jamaoncol.2021.3585

    Corresponding Author: Luis A. Diaz Jr, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (ldiaz@mskcc.org).

    Author Contributions: Dr Diaz Jr had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Foote and White contributed equally to this work.

    Concept and design: Foote, White, Diaz Jr.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Foote, White, Wan, Diaz Jr.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Foote, White, Wan, Rousseau.

    Administrative, technical, or material support: Foote, White, Jee, Pessin.

    Supervision: Foote, Diaz Jr.

    Conflict of Interest Disclosures: Dr White reported personal fees from Memorial Sloan Kettering Cancer Center during the conduct of the study and is the founder and owner of Resphera Biosciences LLC. Dr Jee holds a patent licensed by MDSeq Inc. Dr Argilés has received honoraria for advisory roles from Hoffmann-La Roche, Bayer, Amgen, Merck, Sanofi, and Servier; honoraria for speaking engagements from Hoffmann-La Roche, Bristol Myers Squibb, Bayer, and Servier; travel grants from Hoffmann-La Roche, Bayer, Servier, Amgen, and Merck; and research funds from Bayer. Dr Argilés also serves as an uncompensated advisor for Menarini and Treos Bio Inc. Dr Wan is an inventor of patents for methods for circulating tumor DNA detection. Dr Rousseau reported personal fees from Bayer and Roche, as well as nonfinancial support from Servier outside the submitted work. Dr Diaz Jr is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics; a paid consultant to PGDx, 4Paws Dx, Innovatus Capital Partners, Se’er, Kinnate Biopharma, and NeoPhore; an uncompensated consultant for Merck but has received research support for clinical trials from Merck; an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University, therefore some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins University and Dr Diaz Jr; and an equity holder in PGDx, Delfi Diagnostics, Jounce Therapeutics, Thrive Earlier Detection, and Neophore. No other disclosures were reported.

    Funding/Support: This work is supported by a Stand Up to Cancer Colorectal Cancer Dream Team Translation Research Grant (SU2C-AACR-DT22-17). Dr Foote is partially supported by a Memorial Sloan Kettering Cancer Center/National Institutes of Health grant (T32-CA009512-32) and an American Society of Clinical Oncology Young Investigator Award. Dr Jee is partially supported by a Memorial Sloan Kettering Cancer Center training grant (T32-CA009207).

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    References
    1.
    Hoffmann  M, Kleine-Weber  H, Schroeder  S,  et al.  SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.   Cell. 2020;181(2):271-280.e8. doi:10.1016/j.cell.2020.02.052PubMedGoogle ScholarCrossref
    2.
    Wei  J, Alfajaro  MM, DeWeirdt  PC,  et al.  Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection.   Cell. 2021;184(1):76-91.e13. doi:10.1016/j.cell.2020.10.028PubMedGoogle ScholarCrossref
    3.
    Walls  AC, Park  YJ, Tortorici  MA, Wall  A, McGuire  AT, Veesler  D.  Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.   Cell. 2020;181(2):281-292.e6. doi:10.1016/j.cell.2020.02.058PubMedGoogle ScholarCrossref
    4.
    Jee  J, Foote  MB, Lumish  M,  et al.  Chemotherapy and COVID-19 outcomes in patients with cancer.   J Clin Oncol. 2020;38(30):3538-3546. doi:10.1200/JCO.20.01307PubMedGoogle ScholarCrossref
    5.
    Zoufaly  A, Poglitsch  M, Aberle  JH,  et al.  Human recombinant soluble ACE2 in severe COVID-19.   Lancet Respir Med. 2020;8(11):1154-1158. doi:10.1016/S2213-2600(20)30418-5PubMedGoogle ScholarCrossref
    6.
    Lei  C, Qian  K, Li  T,  et al.  Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig.   Nat Commun. 2020;11(1):2070. doi:10.1038/s41467-020-16048-4PubMedGoogle ScholarCrossref
    7.
    Dyall  J, Coleman  CM, Hart  BJ,  et al.  Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection.   Antimicrob Agents Chemother. 2014;58(8):4885-4893. doi:10.1128/AAC.03036-14PubMedGoogle ScholarCrossref
    8.
    Roschewski  M, Lionakis  MS, Sharman  JP,  et al.  Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.   Sci Immunol. 2020;5(48):eabd0110. doi:10.1126/sciimmunol.abd0110PubMedGoogle Scholar
    9.
    Singh  TU, Parida  S, Lingaraju  MC, Kesavan  M, Kumar  D, Singh  RK.  Drug repurposing approach to fight COVID-19.   Pharmacol Rep. 2020;72(6):1479-1508. doi:10.1007/s43440-020-00155-6PubMedGoogle ScholarCrossref
    10.
    Karam  BS, Morris  RS, Bramante  CT,  et al.  mTOR inhibition in COVID-19: a commentary and review of efficacy in RNA viruses.   J Med Virol. 2021;93(4):1843-1846. doi:10.1002/jmv.26728PubMedGoogle ScholarCrossref
    11.
    Kindrachuk  J, Ork  B, Hart  BJ,  et al.  Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis.   Antimicrob Agents Chemother. 2015;59(2):1088-1099. doi:10.1128/AAC.03659-14PubMedGoogle ScholarCrossref
    12.
    Appelberg  S, Gupta  S, Svensson Akusjärvi  S,  et al.  Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells.   Emerg Microbes Infect. 2020;9(1):1748-1760. doi:10.1080/22221751.2020.1799723PubMedGoogle ScholarCrossref
    13.
    Zhou  Y, Hou  Y, Shen  J, Huang  Y, Martin  W, Cheng  F.  Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2.   Cell Discov. 2020;6(1):14. doi:10.1038/s41421-020-0153-3PubMedGoogle ScholarCrossref
    14.
    Keenan  AB, Jenkins  SL, Jagodnik  KM,  et al.  The Library of Integrated Network-Based Cellular Signatures NIH program: system-level cataloging of human cells response to perturbations.   Cell Syst. 2018;6(1):13-24. doi:10.1016/j.cels.2017.11.001PubMedGoogle ScholarCrossref
    15.
    Duarte  MBO, Leal  F, Argenton  JLP, Carvalheira  JBC.  Outcomes of COVID-19 patients under cytotoxic cancer chemotherapy in Brazil.   Cancers (Basel). 2020;12(12):E3490. doi:10.3390/cancers12123490PubMedGoogle Scholar
    ×