Cellular rewiring in lethal prostate cancer: the architect of drug resistance

• Published in: Nature reviews. Urology 2020-05, Vol.17 (5), p.292-307
• Main Authors: Carceles-Cordon, Marc, Kelly, W. Kevin, Gomella, Leonard, Knudsen, Karen E., Rodriguez-Bravo, Veronica, Domingo-Domenech, Josep
• Format: Article
• Language: English
• Subjects: 631/67/1059; 631/67/1059/153; 631/67/589/466; 631/80/86; Analysis; Cancer cells; Care and treatment; Diagnosis; Drug resistance; Drug Resistance, Neoplasm - physiology; Humans; Immunotherapy; Male; Medicine; Medicine & Public Health; Patient outcomes; Prevention; Prostate cancer; Prostatic Neoplasms - drug therapy; Review Article; Risk factors; Signal Transduction - physiology; Treatment resistance; Urology
• ISSN: 1759-4812; 1759-4820
• DOI: 10.1038/s41585-020-0298-8

Over the past 5 years, the advent of combination therapeutic strategies has substantially reshaped the clinical management of patients with advanced prostate cancer. However, most of these combination regimens were developed empirically and, despite offering survival benefits, are not enough to halt disease progression. Thus, the development of effective therapeutic strategies that target the mechanisms involved in the acquisition of drug resistance and improve clinical trial design are an unmet clinical need. In this context, we hypothesize that the tumour engineers a dynamic response through the process of cellular rewiring, in which it adapts to the therapy used and develops mechanisms of drug resistance via downstream signalling of key regulatory cascades such as the androgen receptor, PI3K–AKT or GATA2-dependent pathways, as well as initiation of biological processes to revert tumour cells to undifferentiated aggressive states via phenotype switching towards a neuroendocrine phenotype or acquisition of stem-like properties. These dynamic responses are specific for each patient and could be responsible for treatment failure despite multi-target approaches. Understanding the common stages of these cellular rewiring mechanisms to gain a new perspective on the molecular underpinnings of drug resistance might help formulate novel combination therapeutic regimens. Management strategies used to treat prostate cancer often lead to treatment resistance, which can arise via a mechanism of cellular rewiring, whereby the tumour cell alters its signalling to escape the effects of therapy. Understanding these mechanisms could enable the development of improved and combination treatment regimens, to minimize treatment failures and improve outcomes. Key points Targeting mechanisms involved in the acquisition of drug resistance could result in more effective therapeutic strategies for patients with prostate cancer. Cellular rewiring can be exploited by prostate cancer cells to acquire drug resistance by implementing alternative bypass signalling pathways after therapy exposure, thus enabling continued tumour proliferation and survival. Tumour cell crosstalk with the microenvironment can also result in cellular rewiring processes that eventually lead to drug resistance. Cellular rewiring mechanisms can induce phenotype switching towards a neuroendocrine phenotype and acquisition of stem-like properties. Clinical trials are investigating the combination of standard ther