We study how kinases regulate breast cancer growth and drug response.
Kinases control nearly all aspects of human biology and are the largest druggable protein class in cancer. We manipulate kinases using next-generation functional genomics tools and study these effects using cell biology, biochemistry, and proteomics. Our goal is to apply these findings to discover new drug targets to prolong the lives of breast cancer patients.
Turning off kinases to accelerate cancer drug discovery
Kinases are one of the most important targets in precision oncology, but the ideal kinase targets for most cancers have not been established. Determining the cellular consequences of turning off kinases has immense potential to transform our understanding of kinases and kinase inhibitors. We are deciphering how kinases regulate cancer cell function by using genome editing to turn off the activity of every kinase in the human genome. This approach will identify novel kinases for therapeutic targeting and will act as a surrogate for small-molecule inhibition to enable drug discovery. We will use this platform to interrogate how kinase activity regulates breast cancer cell growth, sensitivity to targeted therapies, and druggable gene expression. This will compress the interval between kinase hit and lead discovery from decades to years by identifying the optimal mechanisms to inhibit kinases, transforming drug development and the design of combination therapies.
Developing tools to identify new proteomic biomarkers of drug resistance in breast cancer
The response to anticancer therapies is limited by drug resistance, part of which can be explained by tumor genomics (Vasan et al. Nature 2019). In contrast, we have little understanding of how anticancer therapies modulate the tumor proteomes of patients. Recent advances in mass spectrometry now permit unbiased proteomics of formalin-fixed paraffin-embedded (FFPE) tissue, which is how the majority of archival tumor specimens are stored. We are performing proteomic profiling of cohorts of FFPE breast tumors from patients exposed to chemotherapies and targeted therapies, in collaboration with our clinical colleagues, in order to nominate and test new proteomic markers of therapeutic resistance and response.
Solving the PI3K mutational code to tailor PI3K inhibition in breast cancer
PIK3CA is the most frequently mutated oncogene in human cancer and PI3K and AKT inhibitors are a standard of care therapy in PIK3CA mutant breast cancer. However, in most patients, it is unknown which PI3K mutations are activating and/or drug-sensitizing. We have previously characterized double mutations in PI3K which hyperactivate PI3K resulting in increased PI3K and AKT inhibitor sensitivity (Vasan et al. Science 2019, Sivakumar…Sokol, Vasan Clin Cancer Res 2023). We now will comprehensively characterize PI3K protein variants using deep mutational scanning and structural biology. This work will define the repertoire of activating and drug-sensitive patient mutations and will guide the development of mutant-selective PI3K inhibitors.
Discovering and targeting new phosphoprotein drivers of cancer
Functional genomics has identified numerous genetic drivers of cancer, giving rise to a new generation of targeted therapies. While proteins are the primary functional machinery in cells, the vast majority of modified proteins—including phosphoproteins—lack a known kinase or biological function. We aim to illuminate this “dark phosphoproteome” by finding novel substrates of kinases using phosphoproteomics and validating frequent phosphoproteins in cancer. To this end, we have already discovered new frequently phosphorylated substrates including phosphatases, epigenetic modifiers, and metabolic enzymes, which we will functionally characterize to elucidate novel targetable phosphoprotein drivers of cancer.