Abstract SY24-01: Targeting master transcription factor dependency in pediatric cancer

Master transcription factors are regulatory proteins that bind to the genome and establish cell-type specific gene expression programs. They are required for proper multicellular development and are often co-opted to drive oncogenic processes in cancer. In pediatric cancers, master transcription factor deregulation and dependency are hallmarks of these otherwise genetically quiet tumor. Nowhere is this more evident than in neuroblastoma where MYCN amplification singularly defines high risk disease and poor prognosis. Targeting of oncogenic master transcription factors is conceptually attractive as their activity is essential in tumor cells and dispensable in most normal cell types. However as most transcription factors are not considered classically druggable, novel approaches are required to target their activity either directly or indirectly. In this symposia, we will explore mechanisms of master transcription factor deregulation and dependency in pediatric cancers. We and others have shown that almost all oncogenic master transcription factors are driven by super enhancers, large non-coding enhancer elements, and that these master transcription factors are themselves responsible for establishing the tumor cell enhancer and super enhancer landscapes. We will demonstrate how these features of transcriptional regulatory circuitry can be exploited to identify new master transcription factors and tumor dependencies in medulloblastoma, neuroblastoma and other tumor types. We will highlight new chemical and genetic approaches to model and target oncogenic transcription factor regulation including chromatin mediated silencing of non-coding regulatory elements, and degradation based strategies for target perturbation. Finally, we will explore in depth how targeting components of the general transcriptional apparatus such as transcriptional kinases can have surprisingly selective effects on oncogenic transcription factor expression. In our research, we find that CDK9/2 inhibition potently and selectively targets the proliferation of MYCN amplified neuroblastoma with little effect on non MYCN amplified neuroblastoma or normal cells. Selectivity for CDK9 inhibition emerges from its ability to preferentially down-regulate nascent MYCN transcription emanating from the MYCN amplicon. MYCN depletion down regulates gene expression programs associated with neuroblastoma adrenergic/noradrenergic identity and combined with CDK2 inhibition, it strongly induces tumor cell apoptosis in vitro and in vivo. In contrast, MYCN overexpression in non-MYCN amplified neuroblastoma reprograms cells to a more adrenergic state and in turn sensitizes them to CDK9/2 inhibition. These data suggest that MYCN dependent reprogramming of neuroblastoma cell state can be selectively targeted. They also provide a rationale for future clinical exploration of CDK9/2 inhibition in high risk relapse neuroblastoma. From these emerging insights in pediatric cancer as well as from recent pan cancer genetic screening data (e.g. Novartis Project Drive and Broad Achilles) it has become increasingly clear that master transcription factors make for some of the most potent and selective tumor dependencies across a variety of cancers. Transcriptional inhibitors represent an attractive first strategy to indirectly target their expression in a variety of tumor contexts. Although these inhibitors exhibit promising selectivity in pre-clinical models, in most cases they also have pleiotropic effects on transcription in both tumor and normal cells. Ultimately, given the urgent unmet need for therapeutics in aggressive tumors like MYCN amplified neuroblastoma, new strategies will be required to more directly target transcription factor addiction. Citation Format: Charles Lin. Targeting master transcription factor dependency in pediatric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY24-01.