Novel Tumor Suppressing Kinases in Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

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 harbor putative driver mutations. The major focus of this research will be to elucidate novel tumor suppressing 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. A focus for this project is to evaluate novel kinases identified from a motif driven pan-cancer analysis. This strategy utilized 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 MYO3A, 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. So far our initial evaluation indicates MYO3A will be an important and novel tumor suppressing kinase.