The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo.

Sina Jostes,Simon Schneider,Daniel Nettersheim,François Hafezi,Valerie Schumacher,Friedemann Honecker,Glen Kristiansen,Hubert Schorle,Martin Fellermeyer,Matthias Geyer

doi:10.1111/jcmm.13059

Abstract

Type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumours in young men (20–40 years) and are classified as seminoma or non‐seminoma. TGCTs are commonly treated by orchiectomy and chemo‐ or radiotherapy. However, a subset of metastatic non‐seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel treatment options. Recent studies have shown effective application of the small‐molecule inhibitor JQ1 in tumour therapy, which interferes with the function of ‘bromodomain and extraterminal (BET)’ proteins. JQ1‐treated TGCT cell lines display up‐regulation of genes indicative for DNA damage and cellular stress response and induce cell cycle arrest. Embryonal carcinoma (EC) cell lines, which presented as JQ1 sensitive, display down‐regulation of pluripotency factors and induction of mesodermal differentiation. In contrast, seminoma‐like TCam‐2 cells tolerated higher JQ1 concentrations and were resistant to differentiation. ECs xenografted in vivo showed a reduction in tumour size, proliferation rate and angiogenesis in response to JQ1. Finally, the combination of JQ1 and the histone deacetylase inhibitor romidepsin allowed for lower doses and less frequent application, compared with monotherapy. Thus, we propose that JQ1 in combination with romidepsin may serve as a novel therapeutic option for (mixed) TGCTs.

Highlights

Introduction1 of 250 men (age 30–35 years) is diagnosed with TGCT each year [1, 2]
1 of 250 men is diagnosed with TGCT each year [1, 2]
BRD4 mRNA levels appeared slightly lower in cisplatin-resistant cell lines (Fig. 1A)

Summary

Introduction

1 of 250 men (age 30–35 years) is diagnosed with TGCT each year [1, 2]. These tumours presumably result from a block in primordial germ cell differentiation, giving rise to the precursor lesion termed germ cell neoplasia in situ (GCNIS) [3]. A subset of 10–30% of metastatic non-seminomas displays incomplete remission or relapse, due to chemotherapy resistance [2, 7] For these therapyresistant tumours, novel treatment options need to be developed. The cell-permeable small-molecule inhibitor (+)-JQ1 (JQ1) was synthesized, which selectively binds the ‘BET’ family of bromodomain proteins (BRD2, BRD3, BRD4 and BRDT) [8]. JQ1 displaces BET proteins from chromatin, thereby interfering with the mRNA elongation of transcribed loci [8]

Methods

Results

Conclusion