RNASEH2B loss and PARP inhibition in advanced prostate cancer
Juliet Carmichael, … , Adam Sharp, Johann de Bono
Juliet Carmichael, … , Adam Sharp, Johann de Bono
Published June 4, 2024
Citation Information: J Clin Invest. 2024;134(21):e178278. https://doi.org/10.1172/JCI178278.
View: Text | PDF
Clinical Research and Public Health Oncology

RNASEH2B loss and PARP inhibition in advanced prostate cancer

Abstract

BACKGROUND Clinical trials have suggested antitumor activity from PARP inhibition beyond homologous recombination deficiency (HRD). RNASEH2B loss is unrelated to HRD and preclinically sensitizes to PARP inhibition. The current study reports on RNASEH2B protein loss in advanced prostate cancer and its association with RB1 protein loss, clinical outcome, and clonal dynamics during treatment with PARP inhibition in a prospective clinical trial.METHODS Whole tumor biopsies from multiple cohorts of patients with advanced prostate cancer were interrogated using whole-exome sequencing (WES), RNA-Seq (bulk and single nucleus), and IHC for RNASEH2B and RB1. Biopsies from patients treated with olaparib in the TOPARP-A and TOPARP-B clinical trials were used to evaluate RNASEH2B clonal selection during olaparib treatment.RESULTS Shallow codeletion of RNASEH2B and adjacent RB1 — colocated at chromosome 13q14 — was common, deep codeletion infrequent, and gene loss associated with lower mRNA expression. In castration-resistant prostate cancer (CRPC) biopsies, RNASEH2B and RB1 mRNA expression correlated, but single nucleus RNA-Seq indicated discordant loss of expression. IHC studies showed that loss of the 2 proteins often occurred independently, arguably due to stochastic second allele loss. Pre- and posttreatment metastatic CRPC (mCRPC) biopsy studies from BRCA1/2 WT tumors, treated on the TOPARP phase II trial, indicated that olaparib eradicated RNASEH2B-loss tumor subclones.CONCLUSION PARP inhibition may benefit men suffering from mCRPC by eradicating tumor subclones with RNASEH2B loss.TRIAL REGISTRATION Clinicaltrials.gov NCT01682772.FUNDING AstraZeneca; Cancer Research UK; Medical Research Council; Cancer Research UK; Prostate Cancer UK; Movember Foundation; Prostate Cancer Foundation.

Authors

Juliet Carmichael, Ines Figueiredo, Bora Gurel, Nick Beije, Wei Yuan, Jan Rekowski, George Seed, Suzanne Carreira, Claudia Bertan, Maria de Los Dolores Fenor de La Maza, Khobe Chandran, Antje Neeb, Jon Welti, Lewis Gallagher, Denisa Bogdan, Mateus Crespo, Ruth Riisnaes, Ana Ferreira, Susana Miranda, Jinqiu Lu, Michael M. Shen, Emma Hall, Nuria Porta, Daniel Westaby, Christina Guo, Rafael Grochot, Christopher J. Lord, Joaquin Mateo, Adam Sharp, Johann de Bono

×

Figure 1

RNASEH2B and RB1 gene expression in CRPC.

Options: View larger image (or click on image) Download as PowerPoint
RNASEH2B and RB1 gene expression in CRPC. (A) RNASEH2B, RB1 and BRCA2 ar...
(A) RNASEH2B, RB1 and BRCA2 are located in close proximity on chromosome 13. (B) RNASEH2B and RB1 deletions, most frequently shallow, were commonly observed in whole mCRPC biopsies from a RMH whole-exome cohort (n = 93) and lpWGS of plasma DNA from 267 patients treated in 3 clinical trials (FIRSTANA, PROSELICA, and CARD). (C) Scatter plot of RNASEH2B and RB1 mRNA expression (quantile normalized) in the SU2C/PCF (blue) and RMH (red) CRPC cohorts. r and P values were calculated using Spearman correlation. (D) Association between copy number and RNA expression of RB1 and RNASEH2B in the SU2C/PCF (n = 106) and RMH cohorts (n = 87), suggesting that, especially for the latter stage RMH cohort, detectable whole biopsy shallow loss at a DNA level is associated with loss of RNASEH2B expression. Horizontal bars denote IQRs and medians. Combined CNA and RNA expression was only present for a subset of the cohorts as depicted in C. (E) snRNA-Seq of 6 patients with CRPC demonstrating the expression of the RB1 and RNASEH2B gene in a single nucleus. lpWGS, low-pass whole genome sequencing; CNA, copy number alteration; IQR, interquartile range; CRPC, castration resistant prostate cancer; snRNA-Seq, single nucleus RNA-Seq.