John Brognard, Ph.D.

Cancer genomic sequencing has increased our understanding of the temporal and spatial genetic alterations that lead to tumorigenesis, thereby enabling the development of targeted therapies leading to durable and less toxic responses in patients. Mutations that alter kinase activity or pathways involving kinases are common in cancer. However, most research efforts have focused on ~50 kinases among the 538 kinases present in the human kinome. Data from siRNA screens and cancer genomic studies indicate that at least 300 of the unexplored kinases are implicated in cancer and harbor putative driver mutations.

Our research involves defining novel kinase drivers in 3q amplicon-positive squamous cell carcinomas and the mechanisms by which these kinases promote cancer. Our previous work has led us to focus on leucine zipper bearing kinase (LZK, also known as MAP3K13) and TRAF2- and NCK-interacting kinase (TNIK) as therapeutic targets in head and neck squamous cell carcinomas (HNSCCs) and lung squamous cell carcinomas (LSCCs). In addition, we use motif-driven bioinformatic screens across many diverse cancers (pan-cancer) to define novel oncogenic and tumor-suppressing kinases. Combined, these projects will aid in identification of novel kinase drivers of cancer.

We apply diverse approaches to identify cancer-associated kinases and to investigate the signaling pathways regulated by cancer-associated kinases to promote tumorigenesis. These approaches include reverse phase protein arrays (RPPAs) to determine the phosphorylation levels and abundance of proteins, whole-exome sequencing combined with RNAseq to identify genetic mutations in expressed genes, whole-genome sequencing to define copy number alterations, phospho-antibody arrays to globally evaluate activation of signaling pathways, siRNA screens to identify cancer dependencies, molecular dynamics-based modeling of mutations in kinases to provide insight into functional consequences of the mutations and molecular sites for potential therapeutic intervention, and motif-driven, pan-cancer analyses to assess at the kinome level the function of tumor suppressing kinases in cancer. Collectively, this research has and will continue to identify new cancer drivers, targets for therapeutic intervention, and mechanisms of tumorigenesis.