Oncotarget

Research Papers:

Molecular-genetic profiling and high-throughput in vitro drug screening in NUT midline carcinoma—an aggressive and fatal disease

Anja Stirnweiss, Joyce Oommen, Rishi S. Kotecha _, Ursula R. Kees and Alex H. Beesley

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Oncotarget. 2017; 8:112313-112329. https://doi.org/10.18632/oncotarget.22862

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Abstract

Anja Stirnweiss1,2, Joyce Oommen1, Rishi S. Kotecha1,3,4, Ursula R. Kees1 and Alex H. Beesley1

1Leukaemia and Cancer Genetics Program, Telethon Kids Institute, The University of Western Australia, Perth, Australia

2Drug Discovery Group, Telethon Kids Institute, The University of Western Australia, Perth, Australia

3Department of Haematology and Oncology, Princess Margaret Hospital for Children, Perth, Australia

4School of Paediatrics and Child Health, University of Western Australia, Perth, Australia

Correspondence to:

Rishi S. Kotecha, email: rishi.kotecha@health.wa.gov.au

Keywords: NUT midline carcinoma; bromodomain inhibitor; exome sequencing; drug screen; DNA-repair

Received: April 21, 2017     Accepted: November 26, 2017     Published: December 02, 2017

ABSTRACT

NUT midline carcinoma (NMC) is a rare and aggressive cancer, with survival typically less than seven months, that can arise in people of any age. Genetically, NMC is defined by the chromosomal fusion of NUTM1 with a chromatin-binding partner, typically the bromodomain-containing protein BRD4. However, little is known about other genetic aberrations in this disease. In this study, we used a unique panel of cell lines to describe the molecular-genetic features of NMC. Next-generation sequencing identified a recurring high-impact mutation in the DNA-helicase gene RECQL5 in 75% of lines studied, and biological signals from mutation-signature and network analyses consistent with a general failure in DNA-repair. A high-throughput drug screen confirmed that microtubule inhibitors, topoisomerase inhibitors and anthracyclines are highly cytotoxic in the majority of NMC lines, and that cell lines expressing the BRD4-NUTM1 (exon11:exon2) variant are an order of magnitude more responsive to bromodomain inhibitors (iBETs) on average than those with other BRD4-NUTM1 translocation variants. We also identified a highly significant correlation between iBET and aurora kinase inhibitor efficacy in this study. Integration of exome sequencing, transcriptome, and drug sensitivity profiles suggested that aberrant activity of the nuclear receptor co-activator NCOA3 may correlate with poor response to iBETs. In conclusion, our data emphasize the heterogeneity of NMC and highlights genetic aberrations that could be explored to improve therapeutic strategies. The novel finding of a recurring RECQL5 mutation, together with recent reports of chromoplexy in this disease, suggests that DNA-repair pathways are likely to play a central role in NMC tumorigenesis.


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