Differential Kinase Activity across Prostate Tumor Compartments Defines Sensitivity to Target Inhibition

Abstract

Cancer therapy often results in heterogeneous responses in ating EpCAM-low mesenchymal populations with reduced different metastatic lesions in the same patient. Inter- and intrakinase activities; these findings were recapitulated in epithelial tumor heterogeneity in signaling within various tumor compart- and mesenchymal CTC populations in patients with metastatic ments and its impact on therapy are not well characterized due to prostate and breast cancer. Increased kinase activity in EpCAM-the limited sensitivity of single-cell proteomic approaches. To high cells rendered them more sensitive to PI3K/mTOR inhibiovercome this barrier, we applied single-cell mass cytometry with tion, and drug-resistant EpCAM-low populations with reduced a customized 26-antibody panel to PTEN-deleted orthotopic pros-kinase activity emerged over time. Taken together, single-cell tate cancer xenograft models to measure the evolution of kinase proteomics indicate that microenvironment- and cell state–activities in different tumor compartments during metastasis or dependent activation of kinase networks create heterogeneity drug treatment. Compared with primary tumors and circulating and differential drug sensitivity among and within tumor poputumor cells (CTC), bone metastases, but not lung and liver metaslations across different sites, defining a new paradigm of drug tases, exhibited elevated PI3K/mTOR signaling and overexpressed responses to kinase inhibitors. receptor tyrosine kinases (RTK) including c-MET protein. Suppression of c-MET impaired tumor growth in the bone. Intratu-Significance: Single-cell mass cytometry analyses provide moral heterogeneity within tumor compartments also arose from insights into the differences in kinase activities across tumor highly proliferative EpCAM-high epithelial cells with increased compartments and cell states, which contribute to heterogeneous PI3K and mTOR kinase activities coexisting with poorly proliferresponses to targeted therapies.