Martin Whittle
Preceptor - Gary Johnson
No molecularly targeted therapies have been approved for the treatment of basal-like triple negative breast cancer. This subtype comprises approximately 15-20% of breast cancers, and is associated with poor prognosis. Kinases are a major target class for the development of novel molecularly targeted therapies. Recently, MEK1/2 inhibitors were shown to inhibit growth of basal-like breast cancer cell lines; however these MEK1/2 inhibitors are rarely effective as single agents for treating cancer patients due to activation of parallel growth signaling pathways. My project aims to define novel kinase drug targets in basal-like breast cancer that are activated by treatment with the MEK1/2 inhibitor AZD6244. I apply a chemical proteomic approach combining immobilized pan-kinase inhibitors with quantitative mass spectrometry to enrich endogenous kinases from whole cell lysates and measure changes in kinase expression and activity that result from AZD6244 treatment. In a single experiment, up to 50% of the expressed kinome can be enriched and monitored for expression and activity dynamics. I have found that a rapid and stable reprogramming of the kinome is triggered by AZD6244 treatment, and targeting responsive kinases with RNAi or small molecule inhibitors synergistically inhibits proliferation of several triple negative breast cancer cell lines. Using these methods, we rationally selected small molecule inhibitor combinations that potently inhibited tumor growth and induced apoptosis in tumors from the C3-Tag genetically engineered mouse model. Our data suggest that monitoring tumor response to drug treatment is one way to rationally design combination therapies for the effective treatment of triple negative breast cancer.