A prediction of prostate cancer deathsspiking by SARS-CoV-2 infection

ABSTRACT

COVID-19 is a global issue, with over 6.25 million cases in 213 countries and territories on June 1, 2020. Althoughthis virus infects all groups, data indicate that the risk for severe disease and death is much higher in older men, which coincides with the same group of patients at risk for prostate cancer. A recent Italian study investigated theprevalence and severity of COVID-19 in men with prostate cancer. This study indicated that of a total of 4,532 men with COVID-19, from the Veneto region of Italy, 9.5% (n=430) had cancer and out of those around 30% (n=118) hadprostate cancer. Data also indicated that male cancer patients had a 1.8-fold increased risk of COVID-19 infectionand developed a more severe disease. Interestingly, they observed that the prostate cancer patients (n=4) treated with androgen-deprivation therapy (ADT) were less likely to develop COVID-19, and in those who were infected, thedisease was less severe. In this current study, we focused on determining the genetic basis of the higher COVID-19prevalence and severity in male patients and particularly for prostate cancer patients. Researchers found two genesthat are essential for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). ACE2 is a SARS-CoV-2receptor, whereas the serine protease, TMPRSS2, primes the virus for cell entry through cleavage of the viral spikeprotein (S). The expression of TMPRSS2 is significantly high in normal prostate tissue and is regulated in large partby an androgen response element in the promoter region. Therefore, we decided to investigate the status of thesetwo genes in various tumors from The Cancer Genome Atlas (TCGA) database using the cBioportal platform. Weanalyzed over 46,000 tumor samples from 176 studies and found that aggressive metastatic prostate cancer, including neuroendocrine prostate cancer (NEPC), has significantly higher amplification (copy number alteration) ofthe ACE2 and TMPRSS2 genes compared to other cancers. Next, we focused on drugs that could simultaneouslytarget ACE2 or TMPRSS2 and oncogenic pathways and would be beneficial for prostate cancer patients infected with SARS-CoV-2. Although several inhibitors are validated in literature for both ACE2 and TMPRSS2, very limitedstudies were performed to see the effect on cancer cells. Therefore, we analyzed a cytotoxic effect database of over130,000 drugs on NCI-60 cell lines with COMPARE algorithm and found two relevant compounds, NSC-148958 (FT-701) and NSC-280594 (triciribine phosphate), which target ACE2 and TMPRSS2, respectively. Computational dataare currently validating different prostate cancer cell-lines and their response to these drugs. In summary, ourfindings provide the premise that men who are at risk for or diagnosed with prostate cancer may be moresusceptible to severe infection and death in response to SARS-CoV-2 due to the high expression of ACE2 andTMPRSS2, and triciribine phosphate and FT-701 could be a therapeutic intervention to target co-occurrence ofCOVID-19 and prostate cancer.