Potential connections of COVID-19 and prostate cancer – the TMPRSS2 story

Jianyu Rao, MD, Vice Chair, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

There is a strikingly similar pattern of mortality distribution in regards to ethnicity and age between SARS-COV-2 infected patients and prostate cancer patients (1-3). A recent study on 17 million COVID-19 patients found older male, Black and Southern Asian had higher risk of death even after adjustment of other risk factors (4). Similarly, compared with White males, males of Black and South Asia ethnicities are also associated with higher risk of mortality for prostate cancer (5). A possible underlying biological mechanism for such a similarity may be related to androgen receptor pathway (AR), especially TMPRSS2 (6). TMPRSS2 is a gene well-known to tumor biologists. Its regulatory sequences including androgen response elements drive tumorigenesis in a large percentage of prostate cancers (7-9). TMPRSS2 is also up-regulated by androgen in respiratory tract cells including epithelial cells of nasal mucosa, respiratory sinuses, buccal mucosa, tracheal epithelia, and bronchial epithelium, as well as lung type 2 pneumocytes and alveolar macrophages (10-16). Thus, it also plays an important role in COVID-19 disease. SARS-CoV-2 viral entry requires the host cell membrane protein TMPRSS2 (17), which cleaves the Spike protein (a process termed S protein priming) (18) and activates the virus. Activated virus binds to angiotensin-converting enzyme 2 (ACE2) and enters cells for replication (19, 20). The viral replication results in an increased viral load, which may incite both innate and adaptive host immune response (21-23). Recent studies demonstrated that camostat mesylate, a small molecule inhibitor of TMPRSS2, prevented SARS-CoV-2 entry into cultured human lung cells (19). This is consistent with findings that pharmacologic inhibition of TMPRSS2 was sufficient to eliminate lethal SARS-CoV-1 infection in murine models and TMPRSS2 knockout mice were more resistant to SARS-CoV-1 infection than wildtype controls (32). Together, there are strong evidences to support the strategy of targeting TMPRSS2 with androgen deprivation therapy (ADT) for treating COVID-19 patients. In this presentation, we will briefly review the role of TMPRSS2 in prostate cancer and COVID-19 disease processes.