Exploiting Recurrent Chromatin Modifier Mutations for Prostate Cancer Targeted Therapy
Abstract
Purpose: This proposal is focused on exploiting the role of genes/proteins that regulate the structure of chromatin termed chromatin modifiers (CMs) in the context of advanced prostate cancer (PC) particularly involving resistance to therapeutics designed to inhibit androgen receptor (AR) signaling. Scope: This proposal was designed to test the hypothesis that the loss of specific chromatin modifiers (e.g., KDM6A and CREBBP) drive resistance to AR pathway antagonism (e.g. enzalutamide/ENZ). The aims were further designed to test the hypothesis that despite dissimilar protein functions, loss of UTX or other CMs in the same complex or pathway will produce convergent phenotypic and epigenetic changes in cell state that result in resistance to ENZ. Furthermore, these changes can be reversed by pharmacological targeting of specific CMs and epigenetic regulatory factors like EZH2, BRD4, DOT1L, and KDM6B. Three Specific Aims were proposed: AIM 1: Determine the role of chromatin modifier loss in mediating resistance to AR pathway inhibition; AIM 2: Determine the transcriptional and epigenetic alterations that occur due to loss of specific chromatin modifier function in prostate cancer; AIM 3: Evaluate pharmacological approaches to target CM mutant prostate cancer and reverse resistance to AR pathway inhibition. Major Findings: (1) Using genetic/genomic loss of function/knockout screens, we identified multiple CMs that promoted the resistance of PCs to AR antagonism by ENZ; (2) We identified gene expression program alterations resulting from loss of UTX/KDM6A and CBP a key pathway upregulated in this context involved E2F1/cell cycle regulation; (3) Despite a rationally designed drug screen, we did not identify a particular drug capable of differentially targeting PCs with UTX or CBP loss in the context of ENZ treatment; (5) We identified additional factors capable of altering the epigenome and gene expression that contribute to resistance to AR pathway modulation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1203590
Entities
People
- Michael D. Nyquist
Organizations
- Fred Hutchinson Cancer Center