The RNA components of the translation apparatus in prostate cancer plasticity and therapy response

Fred Hutchinson Cancer Center, Seattle WA

Investigators

Abstract

PROJECT SUMMARY Prostate cancer is the second most common malignancy in the United States in men. Early-stage prostate cancer is androgen-dependent and relies on the androgen receptor (AR) signaling pathway for growth and proliferation. Following androgen deprivation therapy (ADT) and AR signaling inhibitors (ARSIs), the disease becomes refractory to AR-targeted therapies through a process known as phenotype switching. In prostate cancer, protein components of the translation apparatus have been shown to promote disease progression and even drug resistance. However, it remains elusive how prostate cancer utilizes RNA components of the protein synthesis machinery to support lineage plasticity and drug resistance. This represents a significant blind spot in our understanding of prostate cancer pathophysiology and an unmet need that has the potential to identify new biomarkers and therapeutic targets. Using state-of-the-art multiplex small RNA sequencing, I have found that lineage plasticity in prostate cancer is characterized by a significant decrease in a single tRNA, Arg-TCT-1-1. I have discovered that Arg-TCT-1-1 drives lineage plasticity through translation regulation of AR regulators enriched for AGA codons using a series of in vitro and in vivo models. In addition, I have conducted the first 5’ UTR tiled CRISPR dropout screen against all major oncogenic and tumor suppressive gene in prostate cancer treated with the ARSI enzalutamide and found that there are select regions within the 5’ UTRs of these genes such as CREBBP, EP300, CHD1, and RB1 which when targeted can drive a synthetic lethality with enzalutamide. Based on these preliminary data, I hypothesize that the RNA components of the translation apparatus (tRNA and 5’ UTRs) are critical in enabling aberrant mRNA specific translation which can drive lineage plasticity and drug resistance. In Aim 1, I will elucidate how Arg-TCT-1-1 tRNA impacts lineage plasticity in prostate cancer. In Aim 2, I will determine the mechanisms by which 5’ UTR-specific mRNA translation promotes treatment resistance in prostate cancer. To achieve these Aims, I will pursue additional training with my primary mentor Dr. Andrew Hsieh (mouse modeling and mRNA translation in prostate cancer), and co-mentors Dr. Tao Pan (tRNA biology), Dr. Michael Haffner (prostate cancer pathology and lineage plasticity), Dr. Alice Berger (functional genomics and computational biology), and Dr. Gabriele Varani (RNA structure biology). Fred Hutchinson Cancer Center is an ideal research environment providing cutting-edge research facilities and opportunities for further career development. With the proposed research and the training, I will be well-positioned to launch my independent research program at an academic institution.