Identifying a Novel Therapeutic Combination Targeting MEK1/2 and KSR1 in Relapsed Neuroblastoma

Background

Neuroblastoma is a cancer of the progenitors of the peripheral nervous system, and is one of the most common types of cancer in pediatric patients. Half of patients diagnosed with neuroblastoma are characterized as high-risk, requiring aggressive multimodal therapy. Nearly 60% of all high-risk patients will develop therapy resistance or relapse. Thus, there is an urgent need for more effective treatment to improve the survival rates of children with relapsed neuroblastoma. The Maris lab has reported that mutations and other genetic aberrations in relapsed neuroblastoma have been shown to cause activation of the RAS-MAPK pathway, which is an elaborate cancer signaling network. The small molecule inhibitor trametinib targets the MEK1/2 protein in this pathway and shows initial efficacy in neuroblastoma cell-based and mouse models, but rapid resistance develops. Therefore, we are interested in identifying potential signaling targets for a novel combinatorial drug strategy.

Project Goal

The Maris lab has performed a screen by knocking down expression of 716 kinases with and without trametinib to identify potential novel drug combinations in neuroblastoma cell lines. Among the list of kinases which most effectively synergized with trametinib was KSR1, which acts as a protein scaffold for the MAPK pathway proteins and is required for pathway activity. I will be focusing on knocking down KSR1 with and without trametinib co-treatment to identify the role of KSR1 in trametinib resistance in neuroblastoma cell lines.  We hypothesize that KSR1 contributes to MEK1/2 inhibitor therapy and that small molecule inhibition of both proteins will yield a more effective therapeutic strategy.