Cancer genomic sequencing has significantly impacted our understanding of the temporal and spatial genetic alterations that lead to tumorigenesis. This information enables the development of targeted therapies that result in durable and less toxic responses in patients. In regard to kinases, the biomedical community has focused research efforts on approximately 200 kinases among the 538 kinases present in the human kinome, yet siRNA screens and cancer genomic studies indicate that the vast majority of these unexplored kinases (approximately 300) are implicated in cancer and harbour putative driver mutations. The major focus of my research will be to elucidate novel cancer-associated kinases in the unexplored kinome, guided by bioinformatics and functional genomic approaches, with an overarching aim of understanding the molecular mechanisms utilized by these kinases to promote tumorigenesis. The lab utilities a multitude of strategies to identify critical pathways required to promote tumorigeneis. These include high-throughput bioinformatics and structural modeling, siRNA screening, and precision genome editing to establish various functional genomic approaches to identify novel drivers. A focus for this project is to perform a motif driven pan-cancer analysis to elucidate the tumour suppressing kinome. This strategy utilities our knowledge of kinases and the requirement for certain kinase motifs to maintain activity (DFG, HRD, APE for example) and our screen has identified several novel kinases enriched for functional mutations. We will take these kinases further, such as GRK7, to assess if this is a novel tumor suppressing kinase. We will study the kinases identified in these screens as follows: General strategy: To determine the functional consequences of somatic mutations in candidate cancer-associated kinases we will carry out a focused, logical and stepwise process. We will begin with biochemical kinase assays and functional analysis by expression of WT (wild type) and mutant kinases in cultured cells, progressing to utilize genome editing to correct mutant alleles and monitoring phenotypic impacts of restoring function of a tumor suppressing kinase, moving on to in vivo tumorigenesis studies, and finally investigating the mechanisms of action. Analysis of somatic mutations in a given kinase will only be continued if promising results are observed at each step. When this is not the case, we will terminate studies on that kinase and proceed to the next top-tier kinase from our bioinformatic analysis.
| Hudson, Andrew M; Stephenson, Natalie L; Li, Cynthia et al. (2018) Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases. Sci Signal 11: |
| Newton, Alexandra C; Brognard, John (2017) Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor. Trends Pharmacol Sci 38:438-447 |
| Marusiak, Anna A; Stephenson, Natalie L; Baik, Hayeon et al. (2016) Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis. Cancer Res 76:724-35 |
