Many patients with
pancreatic cancer have
metastases to distant organs at the time of initial presentation. Recent studies examining the evolution of
pancreatic cancer at the genetic level have shown that clonal complexity of metastatic
pancreatic cancer is already initiated within primary
tumors, and organ-specific
metastases are derived from different subclones. However, we do not yet understand to what extent the evolution of
pancreatic cancer contributes to proteomic and signaling alterations. We hypothesized that genetic heterogeneity of metastatic
pancreatic cancer results in heterogeneity at the
proteome level. To address this, we employed a model system in which cells isolated from three sites of
metastasis (liver, lung, and peritoneum) from a single patient were compared. We used a SILAC-based accurate quantitative proteomic strategy combined with high-resolution mass spectrometry to analyze the total
proteome and
tyrosine phosphoproteome of each of the distal
metastases. Our data revealed distinct patterns of both overall
proteome expression and
tyrosine kinase activities across the three different metastatic lesions. This heterogeneity was significant because it led to differential sensitivity of the neoplastic cells to small molecule inhibitors targeting various
kinases and other pathways. For example, R428, a
tyrosine kinase inhibitor that targets
Axl receptor tyrosine kinase, was able to inhibit cells derived from lung and liver
metastases much more effectively than cells from the peritoneal
metastasis. Finally, we confirmed that administration of R428 in mice bearing xenografts of cells derived from the three different metastatic sites significantly diminished
tumors formed from liver- and lung-
metastasis-derived cell lines as compared with
tumors derived from the peritoneal
metastasis cell line. Overall, our data provide proof-of-principle support that personalized
therapy of multiple organ
metastases in a single patient should involve the administration of a combination of agents, with each agent targeted to the features of different subclones.