Oncogenic Kinases in Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

The lab utilizes a multitude of strategies to identify critical pathways required to promote tumorigenesis. These include high-throughput bioinformatics and structural modelling, siRNA screening, and precision genome editing to establish various functional genomic approaches to identify novel drivers. Utilizing bioinformatics we identify novel kinases enriched for functional mutations to hone in on activated enzymes that can serve as drug targets. We then assess the structural consequences of a subset of mutations in the respective kinases, where crystal structures are available, to determine if the mutations likely increase or decrease catalytic activity. These approaches have been successful in identifying kinases with activating mutations in lung cancer (ABL1 - Testoni et al EMBO Mol. Med.). Going forward we are focused on novel drivers of the 3q amplicon that play a critical role in promoting tumorigenesis in lung squamous cell carcinoma, head and neck cancer, and ovarian cancer (Edwards et al Cancer Research). These novel drivers can serve as targets of therapeutic intervention and an intense effort will focused on the mechanisms by which these amplified kinases or kinases that harbor GOF mutations promote tumorigenesis. In addition, we are studying a novel kinase target that represents a genetic dependency in KRAS mutant lung adenocarcinomas and promotes resistance to ERK inhibitor therapies in melanoma.