New study identifies biological mechanism driving therapy resistance in advanced prostate cancer

A multi-institutional collaborative study led by researchers at the University of Chicago and the Fred Hutchinson Cancer Center has identified a previously unknown biological mechanism that controls cell identity and treatment resistance in advanced prostate cancer.

Published in Nature, the study reveals that a specific transfer RNA (tRNA) named tRNAArg (UCU)-1 plays a central role in allowing prostate cancer cells to escape targeted therapies and transition into more aggressive and treatment-resistant forms of the disease. This finding could help researchers develop a way to re-sensitize resistant tumors to existing therapies.

Treatment resistance in prostate cancer

Prostate cancer, the second-leading cause of cancer death among men in the United States, often depends on androgen receptor signaling for tumor growth. Many tumors initially respond to androgen deprivation therapies and androgen receptor pathway inhibitors like enzalutamide, apalutamide, and darolutamide. Over time, some tumors adapt through a process known as lineage plasticity, where cancer cells lose their dependence on androgen signaling and acquire features of neuroendocrine prostate cancer, a form of cancer that is resistant to therapy.

Tao Pan, PhD, Study Co-Lead Author and Professor, Biochemistry and Molecular Biology, University of ChicagoFor a long time, tRNAs were considered basic housekeeping units, serving as static transfer vehicles of translating the genetic code during protein synthesis. In reality, tRNA levels are dynamically tuned to control cell fate, and the low levels of tRNAArg (UCU)-1 act as a molecular switch that allows prostate cancer cells to escape from the treatment and become a more aggressive type of cancer.”

Pan is also the co-founder of MesoRNA, a UChicago spinout company developing sequencing technologies for small non-coding RNA.

Restoring treatment sensitivity

Therapeutic implications and future research

Current treatment options for treatment-resistant neuroendocrine prostate cancer are largely limited to platinum-based chemotherapies, which offer modest survival benefits. The discovery that tRNA modulation can reverse lineage switching suggests that RNA-targeted therapeutics such as synthetic tRNA mimics or small molecules that enhance tRNAArg (UCU)-1 production, could re-sensitize hard-to-treat tumors to existing, widely available androgen receptor-targeted drugs.

“Unlike DNA mutations where changes are permanent, RNA regulated processes are reversible,” Pan said. “It opens up an unexplored therapeutic landscape focused on modulating RNA dosage and tRNA to overcome drug resistance.”

Source:

University of Chicago Medical Center