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.
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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

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Figure 5

Changes in RNASEH2B expression in patients treated with PARP inhibitor olaparib in TOPARP trials.

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Changes in RNASEH2B expression in patients treated with PARP inhibitor o...
(A) Matched pretreatment and on-treatment biopsies were compared for RNASEH2B expression in patients without an identified BRCA alteration. Pretreatment percentage of RNASEH2B-negative cells are depicted above the waterfall plots. First waterfall plot depicts the absolute change in percentage of RNASEH2B-negative cells (on treatment % minus pretreatment %). Second waterfall plots depicts the percentage change in CTC number (by CellSearch) from pretreatment to 12-weeks of treatment. Tiles below depict which DDR alteration was identified in each specific patient. (B) Exemplar micrographs of RNASEH2B expression by IHC in the 3 cases with the largest percentage change in RNASEH2B-negative cells from pretreatment to on-treatment. IHC depicted here; magnification × 10; scale bar: 100 μm. CTC, circulating tumor cells; IHC, immunohistochemistry; DDR, DNA damage response.