The goal of our research is to build fundamental understanding of how oncogenes disrupt normal homeostatic pathways in cells, in the hopes of translating this knowledge into improved therapeutics for children afflicted with pediatric cancers. The two major focuses of the lab are:

1. Oncogene disruption of cellular DNA repair networks

The DNA damage response (DDR) is a tightly regulated network with built-in redundancies and layers of control. Loss of specific DDR pathways drives oncogenesis in certain cancers (e.g. BRCA mutations), but whether oncogenes, in general, create tumor-specific vulnerabilities within DDR networks is unknown. The need for mechanistic inquiry into oncogene-induced dependencies is particularly acute for the diverse set of transcription factor (TF) fusion-driven cancers, as the oncoproteins have proven intractable drug targets due to the difficulty of direct pharmacologic inhibition. Our work focuses on the FET family of RNA binding proteins (FUS, EWS, TAF15) that are frequent 5’ oncogenic TF fusion partners in a diversity of pediatric sarcomas and leukemias. FET family members are among the earliest proteins recruited to DNA double strand breaks (DSBs), though the functional role of both native FET proteins and FET oncogenic fusions in DSB repair remains poorly defined.

2. Oncogenic kinase fusions and signaling

Our previous work has identified the RAS-MAPK pathway as the major signaling output downstream of the oncogenic kinase fusion protein EML4-ALK in lung cancer (Hrustoanovic et al 2015). While canonical RAS-MAPK pathway actviation requires the presence of a membrane, we have shown that EML4-ALK and other oncogenic kinase fusions are mislocalized by virtue of their fusion partner. Ongoing projects address how the unique subcellular localization of these neomorphic RTK fusions enable RAS-MAPK pathway activation to drive oncogenesis.