Patient-derived models of abiraterone- and enzalutamide-resistant prostate cancer reveal sensitivity to ribosome-directed therapy Academic Article uri icon

abstract

  • 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.

authors

  • Lawrence, MG
  • Obinata, D
  • Sandhu, S
  • Selth, LA
  • Wong, SQ
  • Porter, LH
  • Lister, N
  • Pook, D
  • Pezaro, CJ
  • Goode, DL
  • Rebello, RJ
  • Clark, AK
  • Papargiris, M
  • Van Gramberg, J
  • Hanson, AR
  • Banks, P
  • Wang, H
  • Niranjan, B
  • Keerthikumar, Shivakumar
  • Hedwards, S
  • Huglo, A
  • Yang, R
  • Henzler, C
  • Li, Y
  • Lopez-Campos, F
  • Castro, E
  • Toivanen, R
  • Azad, A
  • Bolton, D
  • Goad, J
  • Grummet, J
  • Harewood, L
  • Kourambas, J
  • Lawrentschuk, Nathan
  • Moon, D
  • Murphy, DG
  • Sengupta, S
  • Snow, R
  • Thorne, H
  • Mitchell, C
  • Pedersen, J
  • Clouston, D
  • Norden, S
  • Ryan, A
  • Dehm, SM
  • Tilley, WD
  • Pearson, RB
  • Hannan, RD
  • Frydenberg, M
  • Furic, L
  • Taylor, RA
  • Risbridger, GP

publication date

  • 2018