Vasan Lab

PIK3CA is the most frequently mutated oncogene in human cancer and PI3K 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 inhibitor sensitivity (Vasan, et al. Science 2019). 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.

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.

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.