Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

Mitchell G. Lawrence, Daisuke Obinata, Shahneen Sandhu, Luke A. Selth, Stephen Q. Wong, Laura H. Porter, Natalie Lister, David Pook, Carmel J. Pezaro, David L. Goode, Richard J. Rebello, Ashlee K. Clark, Melissa Papargiris, Jenna Van Gramberg, Adrienne R. Hanson, Patricia Banks, Hong Wang, Birunthi Niranjan, Shivakumar Keerthikumar, Shelley HedwardsAlisee Huglo, Rendong Yang, Christine Henzler, Yingming Li, Fernando Lopez-Campos, Elena Castro, Roxanne Toivanen, Arun Azad, Damien Bolton, Jeremy Goad, Jeremy Grummet, Laurence Harewood, John Kourambas, Nathan Lawrentschuk, Daniel Moon, Declan G. Murphy, Shomik Sengupta, Ross Snow, Heather Thorne, Catherine Mitchell, John Pedersen, David Clouston, Sam Norden, Andrew Ryan, Scott M. Dehm, Wayne D. Tilley, Richard B. Pearson, Ross D. Hannan, Mark Frydenberg, Luc Furic, Renea A. Taylor, Gail P. Risbridger

Research output: Contribution to journalArticleResearchpeer-review

81 Citations (Scopus)


BACKGROUND: The intractability of castration-resistant prostate cancer (CRPC) is exacerbated by tumour heterogeneity, including diverse alterations to the androgen receptor (AR) axis and AR-independent phenotypes. The availability of additional models encompassing this heterogeneity would facilitate the identification of more effective therapies for CRPC.

OBJECTIVE: To discover therapeutic strategies by exploiting patient-derived models that exemplify the heterogeneity of CRPC.

DESIGN, SETTING, AND PARTICIPANTS: Four new patient-derived xenografts (PDXs) were established from independent metastases of two patients and characterised using integrative genomics. A panel of rationally selected drugs was tested using an innovative ex vivo PDX culture system.

INTERVENTION: The following drugs were evaluated: AR signalling inhibitors (enzalutamide and galeterone), a PARP inhibitor (talazoparib), a chemotherapeutic (cisplatin), a CDK4/6 inhibitor (ribociclib), bromodomain and extraterminal (BET) protein inhibitors (iBET151 and JQ1), and inhibitors of ribosome biogenesis/function (RNA polymerase I inhibitor CX-5461 and pan-PIM kinase inhibitor CX-6258).

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Drug efficacy in ex vivo cultures of PDX tissues was evaluated using immunohistochemistry for Ki67 and cleaved caspase-3 levels. Candidate drugs were also tested for antitumour efficacy in vivo, with tumour volume being the primary endpoint. Two-tailed t tests were used to compare drug and control treatments.

RESULTS AND LIMITATIONS: Integrative genomics revealed that the new PDXs exhibited heterogeneous mechanisms of resistance, including known and novel AR mutations, genomic structural rearrangements of the AR gene, and a neuroendocrine-like AR-null phenotype. Despite their heterogeneity, all models were sensitive to the combination of ribosome-targeting agents CX-5461 and CX-6258.

CONCLUSIONS: This study demonstrates that ribosome-targeting drugs may be effective against diverse CRPC subtypes including AR-null disease, and highlights the potential of contemporary patient-derived models to prioritise treatment strategies for clinical translation.

PATIENT SUMMARY: Diverse types of therapy-resistant prostate cancers are sensitive to a new combination of drugs that inhibit protein synthesis pathways in cancer cells.

Original languageEnglish
Pages (from-to)562-572
Number of pages11
JournalEuropean Urology
Issue number5
Publication statusPublished - 1 Nov 2018


  • Abiraterone
  • Androgen receptor
  • Castration-resistant prostate cancer
  • Enzalutamide
  • Explant
  • Neuroendocrine prostate cancer
  • Organoid
  • Patient-derived xenograft
  • Prostate cancer
  • Ribosome

Cite this