Ependymoma Superenhancer Profiling Reveals Potential Therapeutic Targets

Genomic sequencing has identified molecular targets in many malignancies. However, genomic sequencing has not uncovered effective molecular targets in ependymomas, which are chemotherapy-resistant brain tumors. Mack, Pajtler, Chavez, and colleagues mapped the active chromatin landscape of 42 primary intracranial ependymomas from two independent cohorts using H3K27 acetylation chromatin immunoprecipitation sequencing to identify required superenhancer associated genes. A total of 2,196 and 3,176 superenhancers were identified in the two cohorts, respectively, and there was a large degree of overlap between them. The majority of superenhancers were tumor-specific and not found in normal brain. Identified superenhancers included those with the cancer-associated genes PAX6, SKI, FGFRL1, FGFR1, and BOC, and the known ependymoma oncogenes EPHB2 and CCND1. To identify potential therapeutic targets, the top 15 ependymoma superenhancer genes were knocked down using shRNA, and 60% of the superenhancer genes were found to be required for cell survival. Ependymomas are divided into distinct molecular subgroups, and the active enhancer landscape, covering all six intracranial subgroups, was sufficient to segregate the tumors into these six molecular subgroups. Core regulatory circuitry analysis identified principal ependymoma transcription factors that may serve as therapeutic targets, including SOX9, RFX2, SOX2, ZBTB16, HES1, NFIA, and NFIB. Depletion of SOX9, RFX2, SOX2, and ZBTB16 revealed that these transcription factors are essential for ependymoma cell survival. Further, subtype-specific superenhancer analysis identified ependymoma subtype-specific dependencies. Of the identified superenhancers, HDAC7, EPHA2, FGFR1, and CACNA1H were potentially targetable by available small-molecule inhibitors. Accordingly, treatment with the BET inhibitor JQ1, the FGFR1 inhibitor AZD4547, and the WEE1 inhibitor AZD1775 exhibited antitumor activity in ependymoma intracranial xenografts. Altogether, the characterization of the ependymoma superenhancer landscape reveals potential therapeutic targets not revealed by genomic sequencing.

Mack SC, Pajtler KW, Chavez L, Okonechnikov K, Bertrand KC, Wang X, et al. Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 2018;553:101–5.

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