Successful cancer treatment continues to elude modern medicine and its arsenal of therapeutic strategies. Therapy resistance is driven by tumor heterogeneity, complex interactions between tumor and its microenvironment. Advances in molecular characterization technologies have helped unravel this interaction network and identify therapeutic targets such as tyrosine kinase inhibitors (TKI). However, while tumors may initially respond to TKI therapy, disease progression is inevitable due to acquired resistance. With the ultimate goal of improved molecularly targeted therapeutic efficacy, we have developed and optimized a fluorescence imaging platform termed TRIPODD (Therapeutic Response Imaging through Proteomic and Optical Drug Distribution), resulting in the only methodology capable of simultaneous quantification of single-cell drug target availability and protein expression with preserved spatial context within a tumor. Analysis of preclinical tumor models with TRIPODD enabled discovery of unique cell subpopulations of TKI therapeutic response, where the relationship between drug target availability and therapeutic response was unraveled.
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